Longevity Wiki - User contributions [en-GB]

Calorie restriction

2022-07-13T08:18:23Z

SchmauckMedina: Merged NIA and Wisconsing primate studies as in the Wisconsin section it was largely a discussion about the controversy. There is little content for them to have an independent section.

The physiological decline of an organism, known as aging, is a process highly conserved across the evolutionary tree<ref>Jones, O., Scheuerlein, A., Salguero-Gómez, R., Camarda, C., Schaible, R., & Casper, B. et al. (2013). Diversity of ageing across the tree of life. ''Nature'', ''505''(7482), 169-173. doi: 10.1038/nature12789</ref>. External stressors such as excessive food intake, poor fitness or certain diseases, can accelerate biological aging. Reducing calorie intake significantly below the levels of ''ad libitum'' (feeding without restriction) without malnutrition is commonly referred to as calorie restriction (CR) or dietary restriction (DR).<ref>Bales, C. W., & Kraus, W. E. (2013). Caloric restriction: implications for human cardiometabolic health. ''Journal of cardiopulmonary rehabilitation and prevention'', ''33''(4), 201.</ref>

A number of studies have indicated that CR can increase the lifespan (50-300%) and reduce the onset of age-related diseases in a variety of organisms (e.g. rats, mice, flies, worms, and yeast).<ref name=":0">Flanagan, E. W., Most, J., Mey, J. T., & Redman, L. M. (2020). Calorie Restriction and Aging in Humans. ''Annual Review of Nutrition'', ''40'', 105-133.</ref> There is some evidence from human epidemiological and clinical trial data suggesting that CR could increase healthy lifespan by 1 to 5 years.<ref name=":0" />

Care should be taken when using CR as a means to increase lifespan and prevent age-related diseases. It is important to recognize that scientists point to the benefits of CR only when avoiding malnutrition and when performed under adequate nutrition.<ref>[https://doi.org/10.1016/j.arr.2010.05.002 Cerqueira, F., & Kowaltowski, A. (2010). Commonly adopted caloric restriction protocols often involve malnutrition. ''Ageing Research Reviews'', ''9''(4), 424-430. doi: 10.1016/j.arr.2010.05.002]</ref> Nutrient deficiencies are associated with various health deficits, and consuming less calories than recommended can also be detrimental. There is also concern that reductions in body fat mass could affect muscle bone, and tissue functionality.<ref name=":0" /> Thus, it is important to have sufficient nutrient quality intake along with CR.

Additionally, there are risks related to impaired immune function with CR, which is an example of a potential trade-off.<ref name=":0" /> There may be utility in combining CR with other interventions to maximize healthy longevity, more data is required in both animals and humans.

Several mice studies have shown that different genetic backgrounds may substantially influence the response to CR.<ref name=":5" /> This means that while some mice strains obtain lifespan benefits, others may attain no benefit or even experience harmful consequences.

== Evidence ==
CR is the most widely researched intervention for slowing aging and preventing age-related diseases. A scientist, Clive McCay, first published his groundbreaking research in 1935 – his experiments demonstrated that rats with restricted diets experienced a 33% increase in lifespan.<ref>McCay, C. M., Crowell, M. F., & Maynard, L. A. (1935). The effect of retarded growth upon the length of life span and upon the ultimate body size: one figure. ''The journal of Nutrition'', ''10''(1), 63-79.</ref>

Similar survival experiments have shown that DR can increase the median and maximum lifespan of a variety of other organisms. Below we discuss in more details findings in each species:

=== Worms ===
''Caenorhabditis elegans'' is a roundworm nematode widely used as an aging animal model. Mutations in "''eat''" genes disrupt the function of the pharynx and the feeding behaviour of the worm, leading to partial starvation. These mutations can lengthen the lifespan of worms by up to 50%.<ref>Lakowski, B., & Hekimi, S. (1998). The genetics of caloric restriction in <nowiki>Caenorhabditis elegans</nowiki>. ''Proceedings Of The National Academy Of Sciences'', ''95''(22), 13091-13096. doi: 10.1073/pnas.95.22.13091</ref> The most studied "''eat''" gene in C. elegans, ''eat-2,'' extends lifespan through a mechanism independent of the insulin-signalling pathway, as it does not require the transcription factor [[FOXO longevity genes|''daf-16/FOXO'']] (a central component of the insulin signalling pathway) for the extended lifespan. e''at-2'' is therefore considered a CR-mimetic. e''at-2'' mutants and wild-type worms under caloric restriction do require the transcription factor ''pha-4/FOXA'' for the lifespan-associated phenotype, and more specifically require its expression in intestinal tissue but not in others such as neurons, muscle or hypodermis.<ref>Panowski, S., Wolff, S., Aguilaniu, H. ''et al.'' (2007). PHA-4/Foxa mediates diet-restriction-induced longevity of ''C. elegans''. ''Nature'' 447, 550–555. <nowiki>https://doi.org/10.1038/nature05837</nowiki></ref>

In another study, it was found that when C. ''elegans'' experiences dietary restriction early in development, proteostasis is enhanced and adult lifespan is increased.<ref>Matai, L., Sarkar, G., Chamoli, M., Malik, Y., Kumar, S., & Rautela, U. et al. (2019). Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis. ''Proceedings Of The National Academy Of Sciences'', ''116''(35), 17383-17392. doi: 10.1073/pnas.1900055116</ref> Similarly, both dietary restriction and dietary deprivation (complete removal of food) in adulthood is reported to increase lifespan and to enhance thermotolerance and resistance to oxidative stress.<ref>Lee, G., Wilson, M., Zhu, M., Wolkow, C., de Cabo, R., Ingram, D., & Zou, S. (2006). Dietary deprivation extends lifespan in Caenorhabditis elegans. ''Aging Cell'', ''5''(6), 515-524. doi: 10.1111/j.1474-9726.2006.00241.x</ref>

=== Mice ===
A caloric-restriction experiment was conducted on wild mice to see if they would experience similar results as genetically bred lab mice.<ref>Harper, J., Leathers, C., & Austad, S. (2006). Does caloric restriction extend life in wild mice?. ''Aging Cell'', ''5''(6), 441-449. doi: 10.1111/j.1474-9726.2006.00236.x</ref> The longest-lived wild mouse in the CR test group died at 1601 days old. Comparatively, the oldest wild mouse in the control group died at 1403 days. It is also worth noting that there was no robust longevity difference between the groups, but there was an anticancer effect in the CR group. No differences in longevity between both groups were noted, possibly because wild animals have genetic variation in CR effect, wild animals ate less than ad libitum (without constraint), and wild animals may not have the same CR effect as lab animals.

In another study, it was noted that caloric restriction increased working memory in mice.<ref>Kuhla, A., Lange, S., Holzmann, C., Maass, F., Petersen, J., Vollmar, B., & Wree, A. (2013). Lifelong Caloric Restriction Increases Working Memory in Mice. ''Plos ONE'', ''8''(7), e68778. doi: 10.1371/journal.pone.0068778</ref> Male mice that experienced long periods of fasting between meals were found to live longer and healthier lifespans, regardless of what kinds of food they ate.

The benefits of caloric restriction in mice appear to be affected by the timing of feeding during the day. As nocturnal animals, mice that underwent CR during their normally active feeding period (night time) showed increased health benefits than those undergoing CR during their rest time (daylight), as measured by structural changes in the gut microbiota.<ref>Zhang, L., Xue, X., Zhai, R., Yang, X., Li, H., Zhao, L., & Zhang, C. (2019). Timing of Calorie Restriction in Mice Impacts Host Metabolic Phenotype with Correlative Changes in Gut Microbiota. ''Msystems'', ''4''(6). doi: 10.1128/msystems.00348-19</ref> This showcases the important link between circadian clocks and CR interventions.

Inbred versus non-inbred mice have shown to benefit significantly less from CR interventions, with some inbred mice strains not benefiting at all from CR.<ref>Swindell, W. (2012). Dietary restriction in rats and mice: A meta-analysis and review of the evidence for genotype-dependent effects on lifespan. ''Ageing Research Reviews'', ''11''(2), 254-270. doi: 10.1016/j.arr.2011.12.006</ref> Therefore, this suggests rodent studies might be potentially biased when conducting experiments in laboratory inbred mice and encourages the diversification of CR studies in a wider genetic background.

=== Dogs ===
Caloric restriction has been studied in dogs, where dogs were given 25% dietary restriction as a treatment, compared to the control diet that only differed by quantity of food.<ref name=":6">Greeley, E. H., Ballam, J. M., Harrison, J. M., Kealy, R. D., Lawler, D. F., & Segre, M. (2001). The influence of age and gender on the immune system: a longitudinal study in Labrador Retriever dogs. ''Veterinary immunology and immunopathology'', ''82''(1-2), 57-71.</ref> Over the lifetime, a 1.8 year extension in median lifespan was observed with improved aspects of healthspan, such as delayed osteoarthritis, Various measures of immune function are known to decline with age, but it was found that total lymphocytes, T-cells, and CD8 cells did not decline in the CR group, in contrast to declines seen in the control diet group.<ref name=":6" />

=== Primates ===

==== Restrikal study (2006) ====
The Restrikal study, initiated in 2006, studied the effect of chronic 30% CR in the grey mouse lemur primate, ''Microcebus murinus''.<ref name=":4">Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., ... & Aujard, F. (2018). Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. ''Communications biology'', ''1''(1), 1-8.</ref> Results of the study indicated that CR prolonged lifespan by 50%, from 6.4 to 9.6 years, but affected brain structural integrity.<ref name=":4" /> It was observed that gray matter integrity in the cerebrum was compromised by CR, yet importantly, this did not result in any apparent changes to cognitive function.

==== NIA (2012) & Wisconsin NPRC (2014) Studies Controversy ====
The National Institute on Aging (NIA) study in Maryland, USA, performed CR in rhesus monkeys and saw no differences between survival of monkeys fed control versus calorie-restricted diets.<ref>Mattison, J. A., Roth, G. S., Beasley, T. M., Tilmont, E. M., Handy, A. M., Herbert, R. L., ... & De Cabo, R. (2012). Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. ''Nature'', ''489''(7415), 318-321.</ref> The diet of controls in this study was not reported as fully ''ad libitum'', but rather control monkeys were subject to a slight dietary restriction to prevent obesity.

On the other hand, in the Wisconsin National Primate Research Centre (WNPRC) study, rhesus monkeys were subjected to long-term 30% dietary restriction showed a significantly reduced risk of all-cause mortality and age-related mortality compared to control group monkeys. This suggesting the benefits of CR on aging might be conserved in primates.<ref>Colman, R. J., Beasley, T. M., Kemnitz, J. W., Johnson, S. C., Weindruch, R., & Anderson, R. M. (2014). Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. ''Nature communications'', ''5''(1), 1-5.</ref>

Given that both the Wisconsin and NIA primate studies aimed to investigate calorie restriction as an intervention to slow aging, researchers have attempted to determine why slowed aging was only demonstrated in the Wisconsin study. The observed differences between these two studies is particularly controversial because the control primates in the NIA study lived longer than the CR group in the Wisconsin study, suggesting potential differences in methodology played an important role.

Some have suggested that diet composition is important, due to clear differences in feeding quality and composition between the Wisconsin and NIA studies. A key difference is certainly the fact that the Wisconsin study subjected monkeys to strict ''ad libitum'' in the control group, whilst the NIA study did not in order to prevent obesity, the latter being considered a better controlled experiment.

=== Humans ===
There is currently no definite evidence that calorie restriction extends healthy human lifespan.<ref name=":5">Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref> However, there is early clinical evidence suggesting that CR without malnutrition may lead to various health benefits related to aging, based on several randomized controlled trials. In these human studies, CR is defined as a restriction of calories of ≥10% compared to feeding without restriction (''ad libitum'').

'''The Population of Okinawa'''

Studies into certain populations known for their exceptional longevity, such as in Okinawa - a small island of Japan - have provided some insights into potential lifestyle determinants of longevity. Okinawans have long been recognised as one of the most long-lived populations on the planet, and this is typically attributed to their diet (fish and vegetables). However, more recently, some attention in the scientific community has deviated from the contents of Okinawan’s diets and focused, instead, on their caloric deficits. Six generations of Okinawans aged 65+ were studied; their diet composition, energy intake and expenditure, and survival patterns were analyzed, among many other factors. The results lent support to the wide-ranging health benefits of caloric restriction in humans. Some researchers have speculated that the introduction of Westernized diets may in part explain recent decreases in Okinawan population lifespan.<ref name=":0" />

'''Biosphere-II'''

The Biosphere II experiment was an ecological investigation that provided an unexpected opportunity to measure the effects of CR.<ref>Walford, R., Mock, D., Verdery, R., & MacCallum, T. (2002). Calorie Restriction in Biosphere 2: Alterations in Physiologic, Hematologic, Hormonal, and Biochemical Parameters in Humans Restricted for a 2-Year Period. ''The Journals Of Gerontology Series A: Biological Sciences And Medical Sciences'', ''57''(6), B211-B224. doi: 10.1093/gerona/57.6.b211</ref> Eight volunteers were kept in an ecological ecosystem for two years and allowed to harvest 85% of their food. The food consisted mainly of fruits, vegetables, grains and minimal protein. During the experiment, because of food scarcity, the energy intake of the volunteers decreased by 38% for 6 months. After leaving the experiment the volunteers had a 6% slowing of metabolism which lasted for another 6 months.

Years later, a Biosphere-II participant founded the ''CR Society International,'' which consists of a group of volunteers that have chosen to restrict their calorie intake around 30% for a period of 3 to 15 years.<ref>Fontana, L., Meyer, T., Klein, S., & Holloszy, J. (2004). Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. ''Proceedings Of The National Academy Of Sciences'', ''101''(17), 6659-6663. doi: 10.1073/pnas.0308291101</ref> Individuals of the CR society are leaner, have lower body fat, better cardiometabolic health and lower inflammation. However, this data is sparse and largely limited to self-reports.

'''CALERIE trials'''

The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) research network has produced one of the most rigorous clinical studies conducted in humans. Over a period of nine years, three pilot trials were conducted followed by a randomized study (CALERIE 2).<ref name=":1">Kraus, W. E., Bhapkar, M., Huffman, K. M., Pieper, C. F., Das, S. K., Redman, L. M., ... & CALERIE Investigators. (2019). 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. ''The lancet Diabetes & endocrinology'', ''7''(9), 673-683.</ref><ref name=":2">Rickman, A. D., Williamson, D. A., Martin, C. K., Gilhooly, C. H., Stein, R. I., Bales, C. W., ... & Das, S. K. (2011). The CALERIE Study: design and methods of an innovative 25% caloric restriction intervention. ''Contemporary clinical trials'', ''32''(6), 874-881.</ref>

During phase 1 of the trial, three differing degrees of CR (20%, 25%, and 30%) were tested on a variety of age groups with an overweight BMI status. The trial lasted for 6 – 12 months, and the studies were used to develop and advance the following Phase 2 trial.

In Phase 2 of CALERIE, participants were able to restrict caloric intake by 11.9% and experienced ~10% weight loss over two years, despite the identified target of 25% CR. It must be noted that the level of CR achieved in this study required intensive intervention, involving personalized treatments, algorithmic/computer tracking, and various educational initiatives.<ref name=":2" /> Therefore, the feasibility of such a CR intervention in the real world is something that remains uncharacterized. However, despite participants in the CR group achieving a lower CR target than intended, various improvements to health were noted. The trial resulted in lower levels of T3 and TNF- ɑ, while also reducing certain cardiometabolic risk factors.<ref name=":1" />

Additional analyses suggested a slow down in biological aging rate, and found that weight loss did not appear to account for these effects.<ref name=":3">Belsky, D. W., Huffman, K. M., Pieper, C. F., Shalev, I., & Kraus, W. E. (2018). Change in the rate of biological aging in response to caloric restriction: CALERIE Biobank analysis. ''The Journals of Gerontology: Series A'', ''73''(1), 4-10.</ref> The authors highlight that, based on prior knowledge that a divergence in biological aging trajectories can be observed as early as early adulthood, CR may be more effective in humans when started young.<ref>Belsky, D. W., Caspi, A., Houts, R., Cohen, H. J., Corcoran, D. L., Danese, A., ... & Moffitt, T. E. (2015). Quantification of biological aging in young adults. ''Proceedings of the National Academy of Sciences'', ''112''(30), E4104-E4110.</ref> Moreover, potential CR-related toxicities were posited to be better tolerated in younger adults.<ref name=":3" />

'''CR and immune function - randomized controlled trial'''

One clinical study investigated moderate CR versus ''ad-libitum'' feeding over 2 years. It was found that CR without malnutrition may induce health benefits without impairing cell-mediated immunity or increasing infection risk in non-obese humans.<ref>Meydani, S. N., Das, S. K., Pieper, C. F., Lewis, M. R., Klein, S., Dixit, V. D., ... & Fontana, L. (2016). Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans. ''Aging (Albany NY)'', ''8''(7), 1416.</ref>

'''CR and Intermittent Fasting'''

A recent study in China randomised 139 obese adults to either calorie restriction alone or to calorie restriction with time-restricted eating (a 16-hour intermittent fast and a 8-hour period for eating).<ref>Liu, D., Huang, Y., Huang, C., Yang, S., Wei, X., & Zhang, P. et al. (2022). Calorie Restriction with or without Time-Restricted Eating in Weight Loss. ''New England Journal Of Medicine'', ''386''(16), 1495-1504. doi: 10.1056/nejmoa2114833</ref> After one year, both groups had lost 7-10% of body weight and showed healthier markers for blood sugar, blood fat levels and insulin sensitivity. However, there was no statistically significant difference between both groups, suggesting calorie restriction is responsible for the health-associated benefits and that intermittent fasting has no added benefits to CR diets.

== Underlying biological mechanisms ==
Taking extra calories can lead to cellular glycotoxicity and lipotoxicity, which causes inflammation and oxidative stress and thus increases the risk of age-related diseases (e.g. cancer, diabetes, cardiovascular disorders).<ref name=":0" /> Evidence suggests that CR may have a number of health benefits including preserving cognition, protecting colon health and protecting against arthritis, amongst other benefits:

* Decrease in the systemic risk factors for cardiovascular disease (glucose levels, blood pressure, plasma lipid levels).
* Alteration in the sympathetic nervous system, as well as the neuroendocrine system in lab animals and, sometimes, humans.
* Reduction in oxidative damage due to a decreased production of Reactive Oxygen Species (ROS).
* Increase in CoQ-dependent reductases within the plasma membrane, thus protecting phospholipids and preventing the lipid peroxidation reaction progression.
* Inhibition of mTOR pathway and consequent induction of a[[Autophagy|utophagy]], a specific process that recycles cellular waste.
* Activation of known pro-longevity pathways such as FOXO/AMPK/SIRT, which are evolutionarily conserved across various species.

== Controversies of calorie restriction research ==
There are several criticisms against CR, some of which are highlighted by Sohal and Forster (2014) in “''Caloric Restriction and the Aging Process: A Critique''”.<ref>Sohal, R. S., & Forster, M. J. (2014). Caloric restriction and the aging process: a critique. ''Free radical biology & medicine'', ''73'', 366–382. <nowiki>https://doi.org/10.1016/j.freeradbiomed.2014.05.015</nowiki></ref> The authors highlight that there is a large disparity in CR-related longevity increases: namely, that longevity effects are not universal and sometimes are not shared by different genetic strains of the same species. Moreover, the control animals in the widely-cited caloric restriction studies were fed ''ad libitum'', causing them to become overweight and vulnerable to disease and early deaths. Therefore the relative benefit in the CR group was exaggerated compared to control subjects. In other words, animals with CR diets appear to live relatively longer because the control animals were dying from complications of excess feeding.

Another challenge related to CR as an effective intervention for human aging is the difficulty in compliance over long periods of time.<ref name=":0" /> Concerns over mental and sexual health have also been raised with more severe CR. There are concerns over the loss of weight and fat mass in younger people practicing CR. Exercising along with CR and good nutrition (high protein diet) appears to be highly beneficial for loss of free fat.<ref name=":0" /> New nutritional approaches such as intermittent fasting have emerged. However, there is comparatively limited research on the topic, with CR being the most well-studied nutritional intervention for healthy aging. Furthermore, worms that were treated with Allantoin, rapamycin, TSA, and LY-294002 had a reduced decline in pharyngeal pumping, which indicates a slower rate of aging. Thus, the study uncovered that not only could drug treatments increase longevity but they could also improve the organism’s healthfulness.

It is important to note that researchers are growingly becoming aware that CR or strict intermittent fasting is not a “one size fits all”, but rather an efficient strategy for certain individuals in specific metabolic contexts. For instance, some studies have shown that two people's glucose responses are significantly different even after eating the same food.<ref>Zeevi, D., Korem, T., Zmora, N., Israeli, D., Rothschild, D., & Weinberger, A. et al. (2015). Personalized Nutrition by Prediction of Glycemic Responses. ''Cell'', ''163''(5), 1079-1094. doi: 10.1016/j.cell.2015.11.001</ref> Supporting these findings, companies like [https://www.lumen.me/metabolic-flexibility Lumen Metabolism] and [https://www.levelshealth.com Levels] are offering personalised dietary recommendations based on the measurement of an individuals’s [[metabolic flexibility]].

Similar to non-human primates, the effects of CR on lifespan remain controversial in humans. However, what seems clear from obesity studies is that eating too much results in poor health and decreased longevity.<ref>Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., Chahory, S., Cordonnier, N., Desquilbet, L., Hurion, M. and Zahariev, A., 2018. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. ''Communications biology'', ''1''(1), pp.1-8.</ref>
<references />
[[Category:Longevity]]

Calorie restriction

2022-07-13T08:12:58Z

SchmauckMedina:

The physiological decline of an organism, known as aging, is a process highly conserved across the evolutionary tree<ref>Jones, O., Scheuerlein, A., Salguero-Gómez, R., Camarda, C., Schaible, R., & Casper, B. et al. (2013). Diversity of ageing across the tree of life. ''Nature'', ''505''(7482), 169-173. doi: 10.1038/nature12789</ref>. External stressors such as excessive food intake, poor fitness or certain diseases, can accelerate biological aging. Reducing calorie intake significantly below the levels of ''ad libitum'' (feeding without restriction) without malnutrition is commonly referred to as calorie restriction (CR) or dietary restriction (DR).<ref>Bales, C. W., & Kraus, W. E. (2013). Caloric restriction: implications for human cardiometabolic health. ''Journal of cardiopulmonary rehabilitation and prevention'', ''33''(4), 201.</ref>

A number of studies have indicated that CR can increase the lifespan (50-300%) and reduce the onset of age-related diseases in a variety of organisms (e.g. rats, mice, flies, worms, and yeast).<ref name=":0">Flanagan, E. W., Most, J., Mey, J. T., & Redman, L. M. (2020). Calorie Restriction and Aging in Humans. ''Annual Review of Nutrition'', ''40'', 105-133.</ref> There is some evidence from human epidemiological and clinical trial data suggesting that CR could increase healthy lifespan by 1 to 5 years.<ref name=":0" />

Care should be taken when using CR as a means to increase lifespan and prevent age-related diseases. It is important to recognize that scientists point to the benefits of CR only when avoiding malnutrition and when performed under adequate nutrition.<ref>[https://doi.org/10.1016/j.arr.2010.05.002 Cerqueira, F., & Kowaltowski, A. (2010). Commonly adopted caloric restriction protocols often involve malnutrition. ''Ageing Research Reviews'', ''9''(4), 424-430. doi: 10.1016/j.arr.2010.05.002]</ref> Nutrient deficiencies are associated with various health deficits, and consuming less calories than recommended can also be detrimental. There is also concern that reductions in body fat mass could affect muscle bone, and tissue functionality.<ref name=":0" /> Thus, it is important to have sufficient nutrient quality intake along with CR.

Additionally, there are risks related to impaired immune function with CR, which is an example of a potential trade-off.<ref name=":0" /> There may be utility in combining CR with other interventions to maximize healthy longevity, more data is required in both animals and humans.

Several mice studies have shown that different genetic backgrounds may substantially influence the response to CR.<ref name=":5" /> This means that while some mice strains obtain lifespan benefits, others may attain no benefit or even experience harmful consequences.

== Evidence ==
CR is the most widely researched intervention for slowing aging and preventing age-related diseases. A scientist, Clive McCay, first published his groundbreaking research in 1935 – his experiments demonstrated that rats with restricted diets experienced a 33% increase in lifespan.<ref>McCay, C. M., Crowell, M. F., & Maynard, L. A. (1935). The effect of retarded growth upon the length of life span and upon the ultimate body size: one figure. ''The journal of Nutrition'', ''10''(1), 63-79.</ref>

Similar survival experiments have shown that DR can increase the median and maximum lifespan of a variety of other organisms. Below we discuss in more details findings in each species:

=== Worms ===
''Caenorhabditis elegans'' is a roundworm nematode widely used as an aging animal model. Mutations in "''eat''" genes disrupt the function of the pharynx and the feeding behaviour of the worm, leading to partial starvation. These mutations can lengthen the lifespan of worms by up to 50%.<ref>Lakowski, B., & Hekimi, S. (1998). The genetics of caloric restriction in <nowiki>Caenorhabditis elegans</nowiki>. ''Proceedings Of The National Academy Of Sciences'', ''95''(22), 13091-13096. doi: 10.1073/pnas.95.22.13091</ref> The most studied "''eat''" gene in C. elegans, ''eat-2,'' extends lifespan through a mechanism independent of the insulin-signalling pathway, as it does not require the transcription factor [[FOXO longevity genes|''daf-16/FOXO'']] (a central component of the insulin signalling pathway) for the extended lifespan. e''at-2'' is therefore considered a CR-mimetic. e''at-2'' mutants and wild-type worms under caloric restriction do require the transcription factor ''pha-4/FOXA'' for the lifespan-associated phenotype, and more specifically require its expression in intestinal tissue but not in others such as neurons, muscle or hypodermis.<ref>Panowski, S., Wolff, S., Aguilaniu, H. ''et al.'' (2007). PHA-4/Foxa mediates diet-restriction-induced longevity of ''C. elegans''. ''Nature'' 447, 550–555. <nowiki>https://doi.org/10.1038/nature05837</nowiki></ref>

In another study, it was found that when C. ''elegans'' experiences dietary restriction early in development, proteostasis is enhanced and adult lifespan is increased.<ref>Matai, L., Sarkar, G., Chamoli, M., Malik, Y., Kumar, S., & Rautela, U. et al. (2019). Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis. ''Proceedings Of The National Academy Of Sciences'', ''116''(35), 17383-17392. doi: 10.1073/pnas.1900055116</ref> Similarly, both dietary restriction and dietary deprivation (complete removal of food) in adulthood is reported to increase lifespan and to enhance thermotolerance and resistance to oxidative stress.<ref>Lee, G., Wilson, M., Zhu, M., Wolkow, C., de Cabo, R., Ingram, D., & Zou, S. (2006). Dietary deprivation extends lifespan in Caenorhabditis elegans. ''Aging Cell'', ''5''(6), 515-524. doi: 10.1111/j.1474-9726.2006.00241.x</ref>

=== Mice ===
A caloric-restriction experiment was conducted on wild mice to see if they would experience similar results as genetically bred lab mice.<ref>Harper, J., Leathers, C., & Austad, S. (2006). Does caloric restriction extend life in wild mice?. ''Aging Cell'', ''5''(6), 441-449. doi: 10.1111/j.1474-9726.2006.00236.x</ref> The longest-lived wild mouse in the CR test group died at 1601 days old. Comparatively, the oldest wild mouse in the control group died at 1403 days. It is also worth noting that there was no robust longevity difference between the groups, but there was an anticancer effect in the CR group. No differences in longevity between both groups were noted, possibly because wild animals have genetic variation in CR effect, wild animals ate less than ad libitum (without constraint), and wild animals may not have the same CR effect as lab animals.

In another study, it was noted that caloric restriction increased working memory in mice.<ref>Kuhla, A., Lange, S., Holzmann, C., Maass, F., Petersen, J., Vollmar, B., & Wree, A. (2013). Lifelong Caloric Restriction Increases Working Memory in Mice. ''Plos ONE'', ''8''(7), e68778. doi: 10.1371/journal.pone.0068778</ref> Male mice that experienced long periods of fasting between meals were found to live longer and healthier lifespans, regardless of what kinds of food they ate.

The benefits of caloric restriction in mice appear to be affected by the timing of feeding during the day. As nocturnal animals, mice that underwent CR during their normally active feeding period (night time) showed increased health benefits than those undergoing CR during their rest time (daylight), as measured by structural changes in the gut microbiota.<ref>Zhang, L., Xue, X., Zhai, R., Yang, X., Li, H., Zhao, L., & Zhang, C. (2019). Timing of Calorie Restriction in Mice Impacts Host Metabolic Phenotype with Correlative Changes in Gut Microbiota. ''Msystems'', ''4''(6). doi: 10.1128/msystems.00348-19</ref> This showcases the important link between circadian clocks and CR interventions.

Inbred versus non-inbred mice have shown to benefit significantly less from CR interventions, with some inbred mice strains not benefiting at all from CR.<ref>Swindell, W. (2012). Dietary restriction in rats and mice: A meta-analysis and review of the evidence for genotype-dependent effects on lifespan. ''Ageing Research Reviews'', ''11''(2), 254-270. doi: 10.1016/j.arr.2011.12.006</ref> Therefore, this suggests rodent studies might be potentially biased when conducting experiments in laboratory inbred mice and encourages the diversification of CR studies in a wider genetic background.

=== Dogs ===
Caloric restriction has been studied in dogs, where dogs were given 25% dietary restriction as a treatment, compared to the control diet that only differed by quantity of food.<ref name=":6">Greeley, E. H., Ballam, J. M., Harrison, J. M., Kealy, R. D., Lawler, D. F., & Segre, M. (2001). The influence of age and gender on the immune system: a longitudinal study in Labrador Retriever dogs. ''Veterinary immunology and immunopathology'', ''82''(1-2), 57-71.</ref> Over the lifetime, a 1.8 year extension in median lifespan was observed with improved aspects of healthspan, such as delayed osteoarthritis, Various measures of immune function are known to decline with age, but it was found that total lymphocytes, T-cells, and CD8 cells did not decline in the CR group, in contrast to declines seen in the control diet group.<ref name=":6" />

=== Primates ===

==== Restrikal study (2006) ====
The Restrikal study, initiated in 2006, studied the effect of chronic 30% CR in the grey mouse lemur primate, ''Microcebus murinus''.<ref name=":4">Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., ... & Aujard, F. (2018). Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. ''Communications biology'', ''1''(1), 1-8.</ref> Results of the study indicated that CR prolonged lifespan by 50%, from 6.4 to 9.6 years, but affected brain structural integrity.<ref name=":4" /> It was observed that gray matter integrity in the cerebrum was compromised by CR, yet importantly, this did not result in any apparent changes to cognitive function.

==== NIA study (2012) ====
The National Institute on Aging (NIA) study in Maryland, USA, performed CR in rhesus monkeys and saw no differences between survival of monkeys fed control versus calorie-restricted diets.<ref>Mattison, J. A., Roth, G. S., Beasley, T. M., Tilmont, E. M., Handy, A. M., Herbert, R. L., ... & De Cabo, R. (2012). Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. ''Nature'', ''489''(7415), 318-321.</ref> The diet of controls in this study was not reported as fully ''ad libitum'', but rather control monkeys were subject to a slight dietary restriction to prevent obesity.

==== Wisconsin NPRC study (2014) ====
In the Wisconsin National Primate Research Centre (WNPRC) study, rhesus monkeys subjected to long-term 30% dietary restriction showed a significantly reduced risk of all-cause mortality and age-related mortality compared to control group monkeys, suggesting the benefits of CR on aging might be conserved in primates.<ref>Colman, R. J., Beasley, T. M., Kemnitz, J. W., Johnson, S. C., Weindruch, R., & Anderson, R. M. (2014). Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. ''Nature communications'', ''5''(1), 1-5.</ref>

Given that both the Wisconsin and NIA primate studies aimed to investigate calorie restriction as an intervention to slow aging, researchers have attempted to determine why slowed aging was only demonstrated in the Wisconsin study. The observed differences between these two studies is particularly controversial because the control primates in the NIA study lived longer than the CR group in the Wisconsin study, suggesting potential differences in methodology played an important role.

Some have suggested that diet composition is important, due to clear differences in feeding quality and composition between the Wisconsin and NIA studies. A key difference is certainly the fact that the Wisconsin study subjected monkeys to strict ''ad libitum'' in the control group, whilst the NIA study did not in order to prevent obesity, the latter being considered a better controlled experiment.

=== Humans ===
There is currently no definite evidence that calorie restriction extends healthy human lifespan.<ref name=":5">Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref> However, there is early clinical evidence suggesting that CR without malnutrition may lead to various health benefits related to aging, based on several randomized controlled trials. In these human studies, CR is defined as a restriction of calories of ≥10% compared to feeding without restriction (''ad libitum'').

'''The Population of Okinawa'''

Studies into certain populations known for their exceptional longevity, such as in Okinawa - a small island of Japan - have provided some insights into potential lifestyle determinants of longevity. Okinawans have long been recognised as one of the most long-lived populations on the planet, and this is typically attributed to their diet (fish and vegetables). However, more recently, some attention in the scientific community has deviated from the contents of Okinawan’s diets and focused, instead, on their caloric deficits. Six generations of Okinawans aged 65+ were studied; their diet composition, energy intake and expenditure, and survival patterns were analyzed, among many other factors. The results lent support to the wide-ranging health benefits of caloric restriction in humans. Some researchers have speculated that the introduction of Westernized diets may in part explain recent decreases in Okinawan population lifespan.<ref name=":0" />

'''Biosphere-II'''

The Biosphere II experiment was an ecological investigation that provided an unexpected opportunity to measure the effects of CR.<ref>Walford, R., Mock, D., Verdery, R., & MacCallum, T. (2002). Calorie Restriction in Biosphere 2: Alterations in Physiologic, Hematologic, Hormonal, and Biochemical Parameters in Humans Restricted for a 2-Year Period. ''The Journals Of Gerontology Series A: Biological Sciences And Medical Sciences'', ''57''(6), B211-B224. doi: 10.1093/gerona/57.6.b211</ref> Eight volunteers were kept in an ecological ecosystem for two years and allowed to harvest 85% of their food. The food consisted mainly of fruits, vegetables, grains and minimal protein. During the experiment, because of food scarcity, the energy intake of the volunteers decreased by 38% for 6 months. After leaving the experiment the volunteers had a 6% slowing of metabolism which lasted for another 6 months.

Years later, a Biosphere-II participant founded the ''CR Society International,'' which consists of a group of volunteers that have chosen to restrict their calorie intake around 30% for a period of 3 to 15 years.<ref>Fontana, L., Meyer, T., Klein, S., & Holloszy, J. (2004). Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. ''Proceedings Of The National Academy Of Sciences'', ''101''(17), 6659-6663. doi: 10.1073/pnas.0308291101</ref> Individuals of the CR society are leaner, have lower body fat, better cardiometabolic health and lower inflammation. However, this data is sparse and largely limited to self-reports.

'''CALERIE trials'''

The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) research network has produced one of the most rigorous clinical studies conducted in humans. Over a period of nine years, three pilot trials were conducted followed by a randomized study (CALERIE 2).<ref name=":1">Kraus, W. E., Bhapkar, M., Huffman, K. M., Pieper, C. F., Das, S. K., Redman, L. M., ... & CALERIE Investigators. (2019). 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. ''The lancet Diabetes & endocrinology'', ''7''(9), 673-683.</ref><ref name=":2">Rickman, A. D., Williamson, D. A., Martin, C. K., Gilhooly, C. H., Stein, R. I., Bales, C. W., ... & Das, S. K. (2011). The CALERIE Study: design and methods of an innovative 25% caloric restriction intervention. ''Contemporary clinical trials'', ''32''(6), 874-881.</ref>

During phase 1 of the trial, three differing degrees of CR (20%, 25%, and 30%) were tested on a variety of age groups with an overweight BMI status. The trial lasted for 6 – 12 months, and the studies were used to develop and advance the following Phase 2 trial.

In Phase 2 of CALERIE, participants were able to restrict caloric intake by 11.9% and experienced ~10% weight loss over two years, despite the identified target of 25% CR. It must be noted that the level of CR achieved in this study required intensive intervention, involving personalized treatments, algorithmic/computer tracking, and various educational initiatives.<ref name=":2" /> Therefore, the feasibility of such a CR intervention in the real world is something that remains uncharacterized. However, despite participants in the CR group achieving a lower CR target than intended, various improvements to health were noted. The trial resulted in lower levels of T3 and TNF- ɑ, while also reducing certain cardiometabolic risk factors.<ref name=":1" />

Additional analyses suggested a slow down in biological aging rate, and found that weight loss did not appear to account for these effects.<ref name=":3">Belsky, D. W., Huffman, K. M., Pieper, C. F., Shalev, I., & Kraus, W. E. (2018). Change in the rate of biological aging in response to caloric restriction: CALERIE Biobank analysis. ''The Journals of Gerontology: Series A'', ''73''(1), 4-10.</ref> The authors highlight that, based on prior knowledge that a divergence in biological aging trajectories can be observed as early as early adulthood, CR may be more effective in humans when started young.<ref>Belsky, D. W., Caspi, A., Houts, R., Cohen, H. J., Corcoran, D. L., Danese, A., ... & Moffitt, T. E. (2015). Quantification of biological aging in young adults. ''Proceedings of the National Academy of Sciences'', ''112''(30), E4104-E4110.</ref> Moreover, potential CR-related toxicities were posited to be better tolerated in younger adults.<ref name=":3" />

'''CR and immune function - randomized controlled trial'''

One clinical study investigated moderate CR versus ''ad-libitum'' feeding over 2 years. It was found that CR without malnutrition may induce health benefits without impairing cell-mediated immunity or increasing infection risk in non-obese humans.<ref>Meydani, S. N., Das, S. K., Pieper, C. F., Lewis, M. R., Klein, S., Dixit, V. D., ... & Fontana, L. (2016). Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans. ''Aging (Albany NY)'', ''8''(7), 1416.</ref>

'''CR and Intermittent Fasting'''

A recent study in China randomised 139 obese adults to either calorie restriction alone or to calorie restriction with time-restricted eating (a 16-hour intermittent fast and a 8-hour period for eating).<ref>Liu, D., Huang, Y., Huang, C., Yang, S., Wei, X., & Zhang, P. et al. (2022). Calorie Restriction with or without Time-Restricted Eating in Weight Loss. ''New England Journal Of Medicine'', ''386''(16), 1495-1504. doi: 10.1056/nejmoa2114833</ref> After one year, both groups had lost 7-10% of body weight and showed healthier markers for blood sugar, blood fat levels and insulin sensitivity. However, there was no statistically significant difference between both groups, suggesting calorie restriction is responsible for the health-associated benefits and that intermittent fasting has no added benefits to CR diets.

== Underlying biological mechanisms ==
Taking extra calories can lead to cellular glycotoxicity and lipotoxicity, which causes inflammation and oxidative stress and thus increases the risk of age-related diseases (e.g. cancer, diabetes, cardiovascular disorders).<ref name=":0" /> Evidence suggests that CR may have a number of health benefits including preserving cognition, protecting colon health and protecting against arthritis, amongst other benefits:

* Decrease in the systemic risk factors for cardiovascular disease (glucose levels, blood pressure, plasma lipid levels).
* Alteration in the sympathetic nervous system, as well as the neuroendocrine system in lab animals and, sometimes, humans.
* Reduction in oxidative damage due to a decreased production of Reactive Oxygen Species (ROS).
* Increase in CoQ-dependent reductases within the plasma membrane, thus protecting phospholipids and preventing the lipid peroxidation reaction progression.
* Inhibition of mTOR pathway and consequent induction of a[[Autophagy|utophagy]], a specific process that recycles cellular waste.
* Activation of known pro-longevity pathways such as FOXO/AMPK/SIRT, which are evolutionarily conserved across various species.

== Controversies of calorie restriction research ==
There are several criticisms against CR, some of which are highlighted by Sohal and Forster (2014) in “''Caloric Restriction and the Aging Process: A Critique''”.<ref>Sohal, R. S., & Forster, M. J. (2014). Caloric restriction and the aging process: a critique. ''Free radical biology & medicine'', ''73'', 366–382. <nowiki>https://doi.org/10.1016/j.freeradbiomed.2014.05.015</nowiki></ref> The authors highlight that there is a large disparity in CR-related longevity increases: namely, that longevity effects are not universal and sometimes are not shared by different genetic strains of the same species. Moreover, the control animals in the widely-cited caloric restriction studies were fed ''ad libitum'', causing them to become overweight and vulnerable to disease and early deaths. Therefore the relative benefit in the CR group was exaggerated compared to control subjects. In other words, animals with CR diets appear to live relatively longer because the control animals were dying from complications of excess feeding.

Another challenge related to CR as an effective intervention for human aging is the difficulty in compliance over long periods of time.<ref name=":0" /> Concerns over mental and sexual health have also been raised with more severe CR. There are concerns over the loss of weight and fat mass in younger people practicing CR. Exercising along with CR and good nutrition (high protein diet) appears to be highly beneficial for loss of free fat.<ref name=":0" /> New nutritional approaches such as intermittent fasting have emerged. However, there is comparatively limited research on the topic, with CR being the most well-studied nutritional intervention for healthy aging. Furthermore, worms that were treated with Allantoin, rapamycin, TSA, and LY-294002 had a reduced decline in pharyngeal pumping, which indicates a slower rate of aging. Thus, the study uncovered that not only could drug treatments increase longevity but they could also improve the organism’s healthfulness.

It is important to note that researchers are growingly becoming aware that CR or strict intermittent fasting is not a “one size fits all”, but rather an efficient strategy for certain individuals in specific metabolic contexts. For instance, some studies have shown that two people's glucose responses are significantly different even after eating the same food.<ref>Zeevi, D., Korem, T., Zmora, N., Israeli, D., Rothschild, D., & Weinberger, A. et al. (2015). Personalized Nutrition by Prediction of Glycemic Responses. ''Cell'', ''163''(5), 1079-1094. doi: 10.1016/j.cell.2015.11.001</ref> Supporting these findings, companies like [https://www.lumen.me/metabolic-flexibility Lumen Metabolism] and [https://www.levelshealth.com Levels] are offering personalised dietary recommendations based on the measurement of an individuals’s [[metabolic flexibility]].

Similar to non-human primates, the effects of CR on lifespan remain controversial in humans. However, what seems clear from obesity studies is that eating too much results in poor health and decreased longevity.<ref>Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., Chahory, S., Cordonnier, N., Desquilbet, L., Hurion, M. and Zahariev, A., 2018. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. ''Communications biology'', ''1''(1), pp.1-8.</ref>
<references />
[[Category:Longevity]]

Calorie restriction

2022-07-13T08:10:44Z

SchmauckMedina: Eat-2 > eat-2

The physiological decline of an organism, known as aging, is a process highly conserved across the evolutionary tree<ref>Jones, O., Scheuerlein, A., Salguero-Gómez, R., Camarda, C., Schaible, R., & Casper, B. et al. (2013). Diversity of ageing across the tree of life. ''Nature'', ''505''(7482), 169-173. doi: 10.1038/nature12789</ref>. External stressors such as excessive food intake, poor fitness or certain diseases, can accelerate biological aging. Reducing calorie intake significantly below the levels of ''ad libitum'' (feeding without restriction) without malnutrition is commonly referred to as calorie restriction (CR) or dietary restriction (DR).<ref>Bales, C. W., & Kraus, W. E. (2013). Caloric restriction: implications for human cardiometabolic health. ''Journal of cardiopulmonary rehabilitation and prevention'', ''33''(4), 201.</ref>

A number of studies have indicated that CR can increase the lifespan (50-300%) and reduce the onset of age-related diseases in a variety of organisms (e.g. rats, mice, flies, worms, and yeast).<ref name=":0">Flanagan, E. W., Most, J., Mey, J. T., & Redman, L. M. (2020). Calorie Restriction and Aging in Humans. ''Annual Review of Nutrition'', ''40'', 105-133.</ref> There is some evidence from human epidemiological and clinical trial data suggesting that CR could increase healthy lifespan by 1 to 5 years.<ref name=":0" />

Care should be taken when using CR as a means to increase lifespan and prevent age-related diseases. It is important to recognize that scientists point to the benefits of CR only when avoiding malnutrition and when performed under adequate nutrition.<ref>[https://doi.org/10.1016/j.arr.2010.05.002 Cerqueira, F., & Kowaltowski, A. (2010). Commonly adopted caloric restriction protocols often involve malnutrition. ''Ageing Research Reviews'', ''9''(4), 424-430. doi: 10.1016/j.arr.2010.05.002]</ref> Nutrient deficiencies are associated with various health deficits, and consuming less calories than recommended can also be detrimental. There is also concern that reductions in body fat mass could affect muscle bone, and tissue functionality.<ref name=":0" /> Thus, it is important to have sufficient nutrient quality intake along with CR.

Additionally, there are risks related to impaired immune function with CR, which is an example of a potential trade-off.<ref name=":0" /> There may be utility in combining CR with other interventions to maximize healthy longevity, more data is required in both animals and humans.

Several mice studies have shown that different genetic backgrounds may substantially influence the response to CR.<ref name=":5" /> This means that while some mice strains obtain lifespan benefits, others may attain no benefit or even experience harmful consequences.

== Evidence ==
CR is the most widely researched intervention for slowing aging and preventing age-related diseases. A scientist, Clive McCay, first published his groundbreaking research in 1935 – his experiments demonstrated that rats with restricted diets experienced a 33% increase in lifespan.<ref>McCay, C. M., Crowell, M. F., & Maynard, L. A. (1935). The effect of retarded growth upon the length of life span and upon the ultimate body size: one figure. ''The journal of Nutrition'', ''10''(1), 63-79.</ref>

Similar survival experiments have shown that DR can increase the median and maximum lifespan of a variety of other organisms. Below we discuss in more details findings in each species:

=== Worms ===
''Caenorhabditis elegans'' is a roundworm nematode widely used as an aging animal model. Mutations in "''eat''" genes disrupt the function of the pharynx and the feeding behaviour of the worm, leading to partial starvation. These mutations can lengthen the lifespan of worms by up to 50%.<ref>Lakowski, B., & Hekimi, S. (1998). The genetics of caloric restriction in <nowiki>Caenorhabditis elegans</nowiki>. ''Proceedings Of The National Academy Of Sciences'', ''95''(22), 13091-13096. doi: 10.1073/pnas.95.22.13091</ref> The most studied "''eat''" gene in C. elegans, ''eat-2,'' extends lifespan through a mechanism independent of the insulin-signalling pathway, as it does not require the transcription factor [[FOXO longevity genes|''daf-16/FOXO'']] (a central component of the insulin signalling pathway) for the extended lifespan. e''at-2'' is therefore considered a CR-mimetic. e''at-2'' mutants and wild-type worms under caloric restriction do require the transcription factor ''pha-4/FOXA'' for the lifespan-associated phenotype, and more specifically require its expression in intestinal tissue but not in others such as neurons, muscle or hypodermis.<ref>Panowski, S., Wolff, S., Aguilaniu, H. ''et al.'' (2007). PHA-4/Foxa mediates diet-restriction-induced longevity of ''C. elegans''. ''Nature'' 447, 550–555. <nowiki>https://doi.org/10.1038/nature05837</nowiki></ref>

In another study, it was found that when C. ''elegans'' experiences dietary restriction early in development, proteostasis is enhanced and adult lifespan is increased.<ref>Matai, L., Sarkar, G., Chamoli, M., Malik, Y., Kumar, S., & Rautela, U. et al. (2019). Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis. ''Proceedings Of The National Academy Of Sciences'', ''116''(35), 17383-17392. doi: 10.1073/pnas.1900055116</ref> Similarly, both dietary restriction and dietary deprivation (complete removal of food) in adulthood is reported to increase lifespan and to enhance thermotolerance and resistance to oxidative stress.<ref>Lee, G., Wilson, M., Zhu, M., Wolkow, C., de Cabo, R., Ingram, D., & Zou, S. (2006). Dietary deprivation extends lifespan in Caenorhabditis elegans. ''Aging Cell'', ''5''(6), 515-524. doi: 10.1111/j.1474-9726.2006.00241.x</ref>

=== Mice ===
A caloric-restriction experiment was conducted on wild mice to see if they would experience similar results as genetically bred lab mice.<ref>Harper, J., Leathers, C., & Austad, S. (2006). Does caloric restriction extend life in wild mice?. ''Aging Cell'', ''5''(6), 441-449. doi: 10.1111/j.1474-9726.2006.00236.x</ref> The longest-lived wild mouse in the CR test group died at 1601 days old. Comparatively, the oldest wild mouse in the control group died at 1403 days. It is also worth noting that there was no robust longevity difference between the groups, but there was an anticancer effect in the CR group. No differences in longevity between both groups were noted, possibly because wild animals have genetic variation in CR effect, wild animals ate less than ad libitum (without constraint), and wild animals may not have the same CR effect as lab animals.

In another study, it was noted that caloric restriction increased working memory in mice.<ref>Kuhla, A., Lange, S., Holzmann, C., Maass, F., Petersen, J., Vollmar, B., & Wree, A. (2013). Lifelong Caloric Restriction Increases Working Memory in Mice. ''Plos ONE'', ''8''(7), e68778. doi: 10.1371/journal.pone.0068778</ref> Male mice that experienced long periods of fasting between meals were found to live longer and healthier lifespans, regardless of what kinds of food they ate.

The benefits of caloric restriction in mice appear to be affected by the timing of feeding during the day. As nocturnal animals, mice that underwent CR during their normally active feeding period (night time) showed increased health benefits than those undergoing CR during their rest time (daylight), as measured by structural changes in the gut microbiota.<ref>Zhang, L., Xue, X., Zhai, R., Yang, X., Li, H., Zhao, L., & Zhang, C. (2019). Timing of Calorie Restriction in Mice Impacts Host Metabolic Phenotype with Correlative Changes in Gut Microbiota. ''Msystems'', ''4''(6). doi: 10.1128/msystems.00348-19</ref> This showcases the important link between circadian clocks and CR interventions.

Inbred versus non-inbred mice have shown to benefit significantly less from CR interventions, with some inbred mice strains not benefiting at all from CR.<ref>Swindell, W. (2012). Dietary restriction in rats and mice: A meta-analysis and review of the evidence for genotype-dependent effects on lifespan. ''Ageing Research Reviews'', ''11''(2), 254-270. doi: 10.1016/j.arr.2011.12.006</ref> Therefore, this suggests rodent studies might be potentially biased when conducting experiments in laboratory inbred mice and encourages the diversification of CR studies in a wider genetic background.

=== Dogs ===
Caloric restriction has been studied in dogs, where dogs were given 25% dietary restriction as a treatment, compared to the control diet that only differed by quantity of food.<ref name=":6">Greeley, E. H., Ballam, J. M., Harrison, J. M., Kealy, R. D., Lawler, D. F., & Segre, M. (2001). The influence of age and gender on the immune system: a longitudinal study in Labrador Retriever dogs. ''Veterinary immunology and immunopathology'', ''82''(1-2), 57-71.</ref> Over the lifetime, a 1.8 year extension in median lifespan was observed with improved aspects of healthspan, such as delayed osteoarthritis, Various measures of immune function are known to decline with age, but it was found that total lymphocytes, T-cells, and CD8 cells did not decline in the CR group, in contrast to declines seen in the control diet group.<ref name=":6" />

=== Primates ===

==== Restrikal study (2006) ====
The Restrikal study, initiated in 2006, studied the effect of chronic 30% CR in the grey mouse lemur primate, ''Microcebus murinus''.<ref name=":4">Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., ... & Aujard, F. (2018). Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. ''Communications biology'', ''1''(1), 1-8.</ref> Results of the study indicated that CR prolonged lifespan by 50%, from 6.4 to 9.6 years, but affected brain structural integrity.<ref name=":4" /> It was observed that gray matter integrity in the cerebrum was compromised by CR, yet importantly, this did not result in any apparent changes to cognitive function. Other studies on rhesus monkeys have also reported an overall positive effect of CR, discussed below.

==== NIA study (2012) ====
The National Institute on Aging (NIA) study in Maryland, USA, performed CR in rhesus monkeys and saw no differences between survival of monkeys fed control versus calorie-restricted diets.<ref>Mattison, J. A., Roth, G. S., Beasley, T. M., Tilmont, E. M., Handy, A. M., Herbert, R. L., ... & De Cabo, R. (2012). Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. ''Nature'', ''489''(7415), 318-321.</ref> The diet of controls in this study was not reported as fully ''ad libitum'', but rather control monkeys were subject to a slight dietary restriction to prevent obesity.

==== Wisconsin NPRC study (2014) ====
In the Wisconsin National Primate Research Centre (WNPRC) study, rhesus monkeys subjected to long-term 30% dietary restriction showed a significantly reduced risk of all-cause mortality and age-related mortality compared to control group monkeys, suggesting the benefits of CR on aging might be conserved in primates.<ref>Colman, R. J., Beasley, T. M., Kemnitz, J. W., Johnson, S. C., Weindruch, R., & Anderson, R. M. (2014). Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. ''Nature communications'', ''5''(1), 1-5.</ref>

Given that both the Wisconsin and NIA primate studies aimed to investigate calorie restriction as an intervention to slow aging, researchers have attempted to determine why slowed aging was only demonstrated in the Wisconsin study. The observed differences between these two studies is particularly controversial because the control primates in the NIA study lived longer than the CR group in the Wisconsin study, suggesting potential differences in methodology played an important role.

Some have suggested that diet composition is important, due to clear differences in feeding quality and composition between the Wisconsin and NIA studies. A key difference is certainly the fact that the Wisconsin study subjected monkeys to strict ''ad libitum'' in the control group, whilst the NIA study did not in order to prevent obesity, the latter being considered a better controlled experiment.

=== Humans ===
There is currently no definite evidence that calorie restriction extends healthy human lifespan.<ref name=":5">Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref> However, there is early clinical evidence suggesting that CR without malnutrition may lead to various health benefits related to aging, based on several randomized controlled trials. In these human studies, CR is defined as a restriction of calories of ≥10% compared to feeding without restriction (''ad libitum'').

'''The Population of Okinawa'''

Studies into certain populations known for their exceptional longevity, such as in Okinawa - a small island of Japan - have provided some insights into potential lifestyle determinants of longevity. Okinawans have long been recognised as one of the most long-lived populations on the planet, and this is typically attributed to their diet (fish and vegetables). However, more recently, some attention in the scientific community has deviated from the contents of Okinawan’s diets and focused, instead, on their caloric deficits. Six generations of Okinawans aged 65+ were studied; their diet composition, energy intake and expenditure, and survival patterns were analyzed, among many other factors. The results lent support to the wide-ranging health benefits of caloric restriction in humans. Some researchers have speculated that the introduction of Westernized diets may in part explain recent decreases in Okinawan population lifespan.<ref name=":0" />

'''Biosphere-II'''

The Biosphere II experiment was an ecological investigation that provided an unexpected opportunity to measure the effects of CR.<ref>Walford, R., Mock, D., Verdery, R., & MacCallum, T. (2002). Calorie Restriction in Biosphere 2: Alterations in Physiologic, Hematologic, Hormonal, and Biochemical Parameters in Humans Restricted for a 2-Year Period. ''The Journals Of Gerontology Series A: Biological Sciences And Medical Sciences'', ''57''(6), B211-B224. doi: 10.1093/gerona/57.6.b211</ref> Eight volunteers were kept in an ecological ecosystem for two years and allowed to harvest 85% of their food. The food consisted mainly of fruits, vegetables, grains and minimal protein. During the experiment, because of food scarcity, the energy intake of the volunteers decreased by 38% for 6 months. After leaving the experiment the volunteers had a 6% slowing of metabolism which lasted for another 6 months.

Years later, a Biosphere-II participant founded the ''CR Society International,'' which consists of a group of volunteers that have chosen to restrict their calorie intake around 30% for a period of 3 to 15 years.<ref>Fontana, L., Meyer, T., Klein, S., & Holloszy, J. (2004). Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. ''Proceedings Of The National Academy Of Sciences'', ''101''(17), 6659-6663. doi: 10.1073/pnas.0308291101</ref> Individuals of the CR society are leaner, have lower body fat, better cardiometabolic health and lower inflammation. However, this data is sparse and largely limited to self-reports.

'''CALERIE trials'''

The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) research network has produced one of the most rigorous clinical studies conducted in humans. Over a period of nine years, three pilot trials were conducted followed by a randomized study (CALERIE 2).<ref name=":1">Kraus, W. E., Bhapkar, M., Huffman, K. M., Pieper, C. F., Das, S. K., Redman, L. M., ... & CALERIE Investigators. (2019). 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. ''The lancet Diabetes & endocrinology'', ''7''(9), 673-683.</ref><ref name=":2">Rickman, A. D., Williamson, D. A., Martin, C. K., Gilhooly, C. H., Stein, R. I., Bales, C. W., ... & Das, S. K. (2011). The CALERIE Study: design and methods of an innovative 25% caloric restriction intervention. ''Contemporary clinical trials'', ''32''(6), 874-881.</ref>

During phase 1 of the trial, three differing degrees of CR (20%, 25%, and 30%) were tested on a variety of age groups with an overweight BMI status. The trial lasted for 6 – 12 months, and the studies were used to develop and advance the following Phase 2 trial.

In Phase 2 of CALERIE, participants were able to restrict caloric intake by 11.9% and experienced ~10% weight loss over two years, despite the identified target of 25% CR. It must be noted that the level of CR achieved in this study required intensive intervention, involving personalized treatments, algorithmic/computer tracking, and various educational initiatives.<ref name=":2" /> Therefore, the feasibility of such a CR intervention in the real world is something that remains uncharacterized. However, despite participants in the CR group achieving a lower CR target than intended, various improvements to health were noted. The trial resulted in lower levels of T3 and TNF- ɑ, while also reducing certain cardiometabolic risk factors.<ref name=":1" />

Additional analyses suggested a slow down in biological aging rate, and found that weight loss did not appear to account for these effects.<ref name=":3">Belsky, D. W., Huffman, K. M., Pieper, C. F., Shalev, I., & Kraus, W. E. (2018). Change in the rate of biological aging in response to caloric restriction: CALERIE Biobank analysis. ''The Journals of Gerontology: Series A'', ''73''(1), 4-10.</ref> The authors highlight that, based on prior knowledge that a divergence in biological aging trajectories can be observed as early as early adulthood, CR may be more effective in humans when started young.<ref>Belsky, D. W., Caspi, A., Houts, R., Cohen, H. J., Corcoran, D. L., Danese, A., ... & Moffitt, T. E. (2015). Quantification of biological aging in young adults. ''Proceedings of the National Academy of Sciences'', ''112''(30), E4104-E4110.</ref> Moreover, potential CR-related toxicities were posited to be better tolerated in younger adults.<ref name=":3" />

'''CR and immune function - randomized controlled trial'''

One clinical study investigated moderate CR versus ''ad-libitum'' feeding over 2 years. It was found that CR without malnutrition may induce health benefits without impairing cell-mediated immunity or increasing infection risk in non-obese humans.<ref>Meydani, S. N., Das, S. K., Pieper, C. F., Lewis, M. R., Klein, S., Dixit, V. D., ... & Fontana, L. (2016). Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans. ''Aging (Albany NY)'', ''8''(7), 1416.</ref>

'''CR and Intermittent Fasting'''

A recent study in China randomised 139 obese adults to either calorie restriction alone or to calorie restriction with time-restricted eating (a 16-hour intermittent fast and a 8-hour period for eating).<ref>Liu, D., Huang, Y., Huang, C., Yang, S., Wei, X., & Zhang, P. et al. (2022). Calorie Restriction with or without Time-Restricted Eating in Weight Loss. ''New England Journal Of Medicine'', ''386''(16), 1495-1504. doi: 10.1056/nejmoa2114833</ref> After one year, both groups had lost 7-10% of body weight and showed healthier markers for blood sugar, blood fat levels and insulin sensitivity. However, there was no statistically significant difference between both groups, suggesting calorie restriction is responsible for the health-associated benefits and that intermittent fasting has no added benefits to CR diets.

== Underlying biological mechanisms ==
Taking extra calories can lead to cellular glycotoxicity and lipotoxicity, which causes inflammation and oxidative stress and thus increases the risk of age-related diseases (e.g. cancer, diabetes, cardiovascular disorders).<ref name=":0" /> Evidence suggests that CR may have a number of health benefits including preserving cognition, protecting colon health and protecting against arthritis, amongst other benefits:

* Decrease in the systemic risk factors for cardiovascular disease (glucose levels, blood pressure, plasma lipid levels).
* Alteration in the sympathetic nervous system, as well as the neuroendocrine system in lab animals and, sometimes, humans.
* Reduction in oxidative damage due to a decreased production of Reactive Oxygen Species (ROS).
* Increase in CoQ-dependent reductases within the plasma membrane, thus protecting phospholipids and preventing the lipid peroxidation reaction progression.
* Inhibition of mTOR pathway and consequent induction of a[[Autophagy|utophagy]], a specific process that recycles cellular waste.
* Activation of known pro-longevity pathways such as FOXO/AMPK/SIRT, which are evolutionarily conserved across various species.

== Controversies of calorie restriction research ==
There are several criticisms against CR, some of which are highlighted by Sohal and Forster (2014) in “''Caloric Restriction and the Aging Process: A Critique''”.<ref>Sohal, R. S., & Forster, M. J. (2014). Caloric restriction and the aging process: a critique. ''Free radical biology & medicine'', ''73'', 366–382. <nowiki>https://doi.org/10.1016/j.freeradbiomed.2014.05.015</nowiki></ref> The authors highlight that there is a large disparity in CR-related longevity increases: namely, that longevity effects are not universal and sometimes are not shared by different genetic strains of the same species. Moreover, the control animals in the widely-cited caloric restriction studies were fed ''ad libitum'', causing them to become overweight and vulnerable to disease and early deaths. Therefore the relative benefit in the CR group was exaggerated compared to control subjects. In other words, animals with CR diets appear to live relatively longer because the control animals were dying from complications of excess feeding.

Another challenge related to CR as an effective intervention for human aging is the difficulty in compliance over long periods of time.<ref name=":0" /> Concerns over mental and sexual health have also been raised with more severe CR. There are concerns over the loss of weight and fat mass in younger people practicing CR. Exercising along with CR and good nutrition (high protein diet) appears to be highly beneficial for loss of free fat.<ref name=":0" /> New nutritional approaches such as intermittent fasting have emerged. However, there is comparatively limited research on the topic, with CR being the most well-studied nutritional intervention for healthy aging. Furthermore, worms that were treated with Allantoin, rapamycin, TSA, and LY-294002 had a reduced decline in pharyngeal pumping, which indicates a slower rate of aging. Thus, the study uncovered that not only could drug treatments increase longevity but they could also improve the organism’s healthfulness.

It is important to note that researchers are growingly becoming aware that CR or strict intermittent fasting is not a “one size fits all”, but rather an efficient strategy for certain individuals in specific metabolic contexts. For instance, some studies have shown that two people's glucose responses are significantly different even after eating the same food.<ref>Zeevi, D., Korem, T., Zmora, N., Israeli, D., Rothschild, D., & Weinberger, A. et al. (2015). Personalized Nutrition by Prediction of Glycemic Responses. ''Cell'', ''163''(5), 1079-1094. doi: 10.1016/j.cell.2015.11.001</ref> Supporting these findings, companies like [https://www.lumen.me/metabolic-flexibility Lumen Metabolism] and [https://www.levelshealth.com Levels] are offering personalised dietary recommendations based on the measurement of an individuals’s [[metabolic flexibility]].

Similar to non-human primates, the effects of CR on lifespan remain controversial in humans. However, what seems clear from obesity studies is that eating too much results in poor health and decreased longevity.<ref>Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., Chahory, S., Cordonnier, N., Desquilbet, L., Hurion, M. and Zahariev, A., 2018. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. ''Communications biology'', ''1''(1), pp.1-8.</ref>
<references />
[[Category:Longevity]]

Calorie restriction

2022-07-13T08:08:55Z

SchmauckMedina: Small change of wording.

The physiological decline of an organism, known as aging, is a process highly conserved across the evolutionary tree<ref>Jones, O., Scheuerlein, A., Salguero-Gómez, R., Camarda, C., Schaible, R., & Casper, B. et al. (2013). Diversity of ageing across the tree of life. ''Nature'', ''505''(7482), 169-173. doi: 10.1038/nature12789</ref>. External stressors such as excessive food intake, poor fitness or certain diseases, can accelerate biological aging. Reducing calorie intake significantly below the levels of ''ad libitum'' (feeding without restriction) without malnutrition is commonly referred to as calorie restriction (CR) or dietary restriction (DR).<ref>Bales, C. W., & Kraus, W. E. (2013). Caloric restriction: implications for human cardiometabolic health. ''Journal of cardiopulmonary rehabilitation and prevention'', ''33''(4), 201.</ref>

A number of studies have indicated that CR can increase the lifespan (50-300%) and reduce the onset of age-related diseases in a variety of organisms (e.g. rats, mice, flies, worms, and yeast).<ref name=":0">Flanagan, E. W., Most, J., Mey, J. T., & Redman, L. M. (2020). Calorie Restriction and Aging in Humans. ''Annual Review of Nutrition'', ''40'', 105-133.</ref> There is some evidence from human epidemiological and clinical trial data suggesting that CR could increase healthy lifespan by 1 to 5 years.<ref name=":0" />

Care should be taken when using CR as a means to increase lifespan and prevent age-related diseases. It is important to recognize that scientists point to the benefits of CR only when avoiding malnutrition and when performed under adequate nutrition.<ref>[https://doi.org/10.1016/j.arr.2010.05.002 Cerqueira, F., & Kowaltowski, A. (2010). Commonly adopted caloric restriction protocols often involve malnutrition. ''Ageing Research Reviews'', ''9''(4), 424-430. doi: 10.1016/j.arr.2010.05.002]</ref> Nutrient deficiencies are associated with various health deficits, and consuming less calories than recommended can also be detrimental. There is also concern that reductions in body fat mass could affect muscle bone, and tissue functionality.<ref name=":0" /> Thus, it is important to have sufficient nutrient quality intake along with CR.

Additionally, there are risks related to impaired immune function with CR, which is an example of a potential trade-off.<ref name=":0" /> There may be utility in combining CR with other interventions to maximize healthy longevity, more data is required in both animals and humans.

Several mice studies have shown that different genetic backgrounds may substantially influence the response to CR.<ref name=":5" /> This means that while some mice strains obtain lifespan benefits, others may attain no benefit or even experience harmful consequences.

== Evidence ==
CR is the most widely researched intervention for slowing aging and preventing age-related diseases. A scientist, Clive McCay, first published his groundbreaking research in 1935 – his experiments demonstrated that rats with restricted diets experienced a 33% increase in lifespan.<ref>McCay, C. M., Crowell, M. F., & Maynard, L. A. (1935). The effect of retarded growth upon the length of life span and upon the ultimate body size: one figure. ''The journal of Nutrition'', ''10''(1), 63-79.</ref>

Similar survival experiments have shown that DR can increase the median and maximum lifespan of a variety of other organisms. Below we discuss in more details findings in each species:

=== Worms ===
''Caenorhabditis elegans'' is a roundworm nematode widely used as an aging animal model. Mutations in "''eat''" genes disrupt the function of the pharynx and the feeding behaviour of the worm, leading to partial starvation. These mutations can lengthen the lifespan of worms by up to 50%.<ref>Lakowski, B., & Hekimi, S. (1998). The genetics of caloric restriction in <nowiki>Caenorhabditis elegans</nowiki>. ''Proceedings Of The National Academy Of Sciences'', ''95''(22), 13091-13096. doi: 10.1073/pnas.95.22.13091</ref> The most studied "''eat''" gene in C. elegans, ''eat-2,'' extends lifespan through a mechanism independent of the insulin-signalling pathway, as it does not require the transcription factor [[FOXO longevity genes|''daf-16/FOXO'']] (a central component of the insulin signalling pathway) for the extended lifespan. ''Eat-2'' is therefore considered a CR-mimetic. ''Eat-2'' mutants and wild-type worms under caloric restriction do require the transcription factor ''pha-4/FOXA'' for the lifespan-associated phenotype, and more specifically require its expression in intestinal tissue but not in others such as neurons, muscle or hypodermis.<ref>Panowski, S., Wolff, S., Aguilaniu, H. ''et al.'' (2007). PHA-4/Foxa mediates diet-restriction-induced longevity of ''C. elegans''. ''Nature'' 447, 550–555. <nowiki>https://doi.org/10.1038/nature05837</nowiki></ref>

In another study, it was found that when C. ''elegans'' experiences dietary restriction early in development, proteostasis is enhanced and adult lifespan is increased.<ref>Matai, L., Sarkar, G., Chamoli, M., Malik, Y., Kumar, S., & Rautela, U. et al. (2019). Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis. ''Proceedings Of The National Academy Of Sciences'', ''116''(35), 17383-17392. doi: 10.1073/pnas.1900055116</ref> Similarly, both dietary restriction and dietary deprivation (complete removal of food) in adulthood is reported to increase lifespan and to enhance thermotolerance and resistance to oxidative stress.<ref>Lee, G., Wilson, M., Zhu, M., Wolkow, C., de Cabo, R., Ingram, D., & Zou, S. (2006). Dietary deprivation extends lifespan in Caenorhabditis elegans. ''Aging Cell'', ''5''(6), 515-524. doi: 10.1111/j.1474-9726.2006.00241.x</ref>

=== Mice ===
A caloric-restriction experiment was conducted on wild mice to see if they would experience similar results as genetically bred lab mice.<ref>Harper, J., Leathers, C., & Austad, S. (2006). Does caloric restriction extend life in wild mice?. ''Aging Cell'', ''5''(6), 441-449. doi: 10.1111/j.1474-9726.2006.00236.x</ref> The longest-lived wild mouse in the CR test group died at 1601 days old. Comparatively, the oldest wild mouse in the control group died at 1403 days. It is also worth noting that there was no robust longevity difference between the groups, but there was an anticancer effect in the CR group. No differences in longevity between both groups were noted, possibly because wild animals have genetic variation in CR effect, wild animals ate less than ad libitum (without constraint), and wild animals may not have the same CR effect as lab animals.

In another study, it was noted that caloric restriction increased working memory in mice.<ref>Kuhla, A., Lange, S., Holzmann, C., Maass, F., Petersen, J., Vollmar, B., & Wree, A. (2013). Lifelong Caloric Restriction Increases Working Memory in Mice. ''Plos ONE'', ''8''(7), e68778. doi: 10.1371/journal.pone.0068778</ref> Male mice that experienced long periods of fasting between meals were found to live longer and healthier lifespans, regardless of what kinds of food they ate.

The benefits of caloric restriction in mice appear to be affected by the timing of feeding during the day. As nocturnal animals, mice that underwent CR during their normally active feeding period (night time) showed increased health benefits than those undergoing CR during their rest time (daylight), as measured by structural changes in the gut microbiota.<ref>Zhang, L., Xue, X., Zhai, R., Yang, X., Li, H., Zhao, L., & Zhang, C. (2019). Timing of Calorie Restriction in Mice Impacts Host Metabolic Phenotype with Correlative Changes in Gut Microbiota. ''Msystems'', ''4''(6). doi: 10.1128/msystems.00348-19</ref> This showcases the important link between circadian clocks and CR interventions.

Inbred versus non-inbred mice have shown to benefit significantly less from CR interventions, with some inbred mice strains not benefiting at all from CR.<ref>Swindell, W. (2012). Dietary restriction in rats and mice: A meta-analysis and review of the evidence for genotype-dependent effects on lifespan. ''Ageing Research Reviews'', ''11''(2), 254-270. doi: 10.1016/j.arr.2011.12.006</ref> Therefore, this suggests rodent studies might be potentially biased when conducting experiments in laboratory inbred mice and encourages the diversification of CR studies in a wider genetic background.

=== Dogs ===
Caloric restriction has been studied in dogs, where dogs were given 25% dietary restriction as a treatment, compared to the control diet that only differed by quantity of food.<ref name=":6">Greeley, E. H., Ballam, J. M., Harrison, J. M., Kealy, R. D., Lawler, D. F., & Segre, M. (2001). The influence of age and gender on the immune system: a longitudinal study in Labrador Retriever dogs. ''Veterinary immunology and immunopathology'', ''82''(1-2), 57-71.</ref> Over the lifetime, a 1.8 year extension in median lifespan was observed with improved aspects of healthspan, such as delayed osteoarthritis, Various measures of immune function are known to decline with age, but it was found that total lymphocytes, T-cells, and CD8 cells did not decline in the CR group, in contrast to declines seen in the control diet group.<ref name=":6" />

=== Primates ===

==== Restrikal study (2006) ====
The Restrikal study, initiated in 2006, studied the effect of chronic 30% CR in the grey mouse lemur primate, ''Microcebus murinus''.<ref name=":4">Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., ... & Aujard, F. (2018). Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. ''Communications biology'', ''1''(1), 1-8.</ref> Results of the study indicated that CR prolonged lifespan by 50%, from 6.4 to 9.6 years, but affected brain structural integrity.<ref name=":4" /> It was observed that gray matter integrity in the cerebrum was compromised by CR, yet importantly, this did not result in any apparent changes to cognitive function. Other studies on rhesus monkeys have also reported an overall positive effect of CR, discussed below.

==== NIA study (2012) ====
The National Institute on Aging (NIA) study in Maryland, USA, performed CR in rhesus monkeys and saw no differences between survival of monkeys fed control versus calorie-restricted diets.<ref>Mattison, J. A., Roth, G. S., Beasley, T. M., Tilmont, E. M., Handy, A. M., Herbert, R. L., ... & De Cabo, R. (2012). Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. ''Nature'', ''489''(7415), 318-321.</ref> The diet of controls in this study was not reported as fully ''ad libitum'', but rather control monkeys were subject to a slight dietary restriction to prevent obesity.

==== Wisconsin NPRC study (2014) ====
In the Wisconsin National Primate Research Centre (WNPRC) study, rhesus monkeys subjected to long-term 30% dietary restriction showed a significantly reduced risk of all-cause mortality and age-related mortality compared to control group monkeys, suggesting the benefits of CR on aging might be conserved in primates.<ref>Colman, R. J., Beasley, T. M., Kemnitz, J. W., Johnson, S. C., Weindruch, R., & Anderson, R. M. (2014). Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. ''Nature communications'', ''5''(1), 1-5.</ref>

Given that both the Wisconsin and NIA primate studies aimed to investigate calorie restriction as an intervention to slow aging, researchers have attempted to determine why slowed aging was only demonstrated in the Wisconsin study. The observed differences between these two studies is particularly controversial because the control primates in the NIA study lived longer than the CR group in the Wisconsin study, suggesting potential differences in methodology played an important role.

Some have suggested that diet composition is important, due to clear differences in feeding quality and composition between the Wisconsin and NIA studies. A key difference is certainly the fact that the Wisconsin study subjected monkeys to strict ''ad libitum'' in the control group, whilst the NIA study did not in order to prevent obesity, the latter being considered a better controlled experiment.

=== Humans ===
There is currently no definite evidence that calorie restriction extends healthy human lifespan.<ref name=":5">Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref> However, there is early clinical evidence suggesting that CR without malnutrition may lead to various health benefits related to aging, based on several randomized controlled trials. In these human studies, CR is defined as a restriction of calories of ≥10% compared to feeding without restriction (''ad libitum'').

'''The Population of Okinawa'''

Studies into certain populations known for their exceptional longevity, such as in Okinawa - a small island of Japan - have provided some insights into potential lifestyle determinants of longevity. Okinawans have long been recognised as one of the most long-lived populations on the planet, and this is typically attributed to their diet (fish and vegetables). However, more recently, some attention in the scientific community has deviated from the contents of Okinawan’s diets and focused, instead, on their caloric deficits. Six generations of Okinawans aged 65+ were studied; their diet composition, energy intake and expenditure, and survival patterns were analyzed, among many other factors. The results lent support to the wide-ranging health benefits of caloric restriction in humans. Some researchers have speculated that the introduction of Westernized diets may in part explain recent decreases in Okinawan population lifespan.<ref name=":0" />

'''Biosphere-II'''

The Biosphere II experiment was an ecological investigation that provided an unexpected opportunity to measure the effects of CR.<ref>Walford, R., Mock, D., Verdery, R., & MacCallum, T. (2002). Calorie Restriction in Biosphere 2: Alterations in Physiologic, Hematologic, Hormonal, and Biochemical Parameters in Humans Restricted for a 2-Year Period. ''The Journals Of Gerontology Series A: Biological Sciences And Medical Sciences'', ''57''(6), B211-B224. doi: 10.1093/gerona/57.6.b211</ref> Eight volunteers were kept in an ecological ecosystem for two years and allowed to harvest 85% of their food. The food consisted mainly of fruits, vegetables, grains and minimal protein. During the experiment, because of food scarcity, the energy intake of the volunteers decreased by 38% for 6 months. After leaving the experiment the volunteers had a 6% slowing of metabolism which lasted for another 6 months.

Years later, a Biosphere-II participant founded the ''CR Society International,'' which consists of a group of volunteers that have chosen to restrict their calorie intake around 30% for a period of 3 to 15 years.<ref>Fontana, L., Meyer, T., Klein, S., & Holloszy, J. (2004). Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. ''Proceedings Of The National Academy Of Sciences'', ''101''(17), 6659-6663. doi: 10.1073/pnas.0308291101</ref> Individuals of the CR society are leaner, have lower body fat, better cardiometabolic health and lower inflammation. However, this data is sparse and largely limited to self-reports.

'''CALERIE trials'''

The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) research network has produced one of the most rigorous clinical studies conducted in humans. Over a period of nine years, three pilot trials were conducted followed by a randomized study (CALERIE 2).<ref name=":1">Kraus, W. E., Bhapkar, M., Huffman, K. M., Pieper, C. F., Das, S. K., Redman, L. M., ... & CALERIE Investigators. (2019). 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. ''The lancet Diabetes & endocrinology'', ''7''(9), 673-683.</ref><ref name=":2">Rickman, A. D., Williamson, D. A., Martin, C. K., Gilhooly, C. H., Stein, R. I., Bales, C. W., ... & Das, S. K. (2011). The CALERIE Study: design and methods of an innovative 25% caloric restriction intervention. ''Contemporary clinical trials'', ''32''(6), 874-881.</ref>

During phase 1 of the trial, three differing degrees of CR (20%, 25%, and 30%) were tested on a variety of age groups with an overweight BMI status. The trial lasted for 6 – 12 months, and the studies were used to develop and advance the following Phase 2 trial.

In Phase 2 of CALERIE, participants were able to restrict caloric intake by 11.9% and experienced ~10% weight loss over two years, despite the identified target of 25% CR. It must be noted that the level of CR achieved in this study required intensive intervention, involving personalized treatments, algorithmic/computer tracking, and various educational initiatives.<ref name=":2" /> Therefore, the feasibility of such a CR intervention in the real world is something that remains uncharacterized. However, despite participants in the CR group achieving a lower CR target than intended, various improvements to health were noted. The trial resulted in lower levels of T3 and TNF- ɑ, while also reducing certain cardiometabolic risk factors.<ref name=":1" />

Additional analyses suggested a slow down in biological aging rate, and found that weight loss did not appear to account for these effects.<ref name=":3">Belsky, D. W., Huffman, K. M., Pieper, C. F., Shalev, I., & Kraus, W. E. (2018). Change in the rate of biological aging in response to caloric restriction: CALERIE Biobank analysis. ''The Journals of Gerontology: Series A'', ''73''(1), 4-10.</ref> The authors highlight that, based on prior knowledge that a divergence in biological aging trajectories can be observed as early as early adulthood, CR may be more effective in humans when started young.<ref>Belsky, D. W., Caspi, A., Houts, R., Cohen, H. J., Corcoran, D. L., Danese, A., ... & Moffitt, T. E. (2015). Quantification of biological aging in young adults. ''Proceedings of the National Academy of Sciences'', ''112''(30), E4104-E4110.</ref> Moreover, potential CR-related toxicities were posited to be better tolerated in younger adults.<ref name=":3" />

'''CR and immune function - randomized controlled trial'''

One clinical study investigated moderate CR versus ''ad-libitum'' feeding over 2 years. It was found that CR without malnutrition may induce health benefits without impairing cell-mediated immunity or increasing infection risk in non-obese humans.<ref>Meydani, S. N., Das, S. K., Pieper, C. F., Lewis, M. R., Klein, S., Dixit, V. D., ... & Fontana, L. (2016). Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans. ''Aging (Albany NY)'', ''8''(7), 1416.</ref>

'''CR and Intermittent Fasting'''

A recent study in China randomised 139 obese adults to either calorie restriction alone or to calorie restriction with time-restricted eating (a 16-hour intermittent fast and a 8-hour period for eating).<ref>Liu, D., Huang, Y., Huang, C., Yang, S., Wei, X., & Zhang, P. et al. (2022). Calorie Restriction with or without Time-Restricted Eating in Weight Loss. ''New England Journal Of Medicine'', ''386''(16), 1495-1504. doi: 10.1056/nejmoa2114833</ref> After one year, both groups had lost 7-10% of body weight and showed healthier markers for blood sugar, blood fat levels and insulin sensitivity. However, there was no statistically significant difference between both groups, suggesting calorie restriction is responsible for the health-associated benefits and that intermittent fasting has no added benefits to CR diets.

== Underlying biological mechanisms ==
Taking extra calories can lead to cellular glycotoxicity and lipotoxicity, which causes inflammation and oxidative stress and thus increases the risk of age-related diseases (e.g. cancer, diabetes, cardiovascular disorders).<ref name=":0" /> Evidence suggests that CR may have a number of health benefits including preserving cognition, protecting colon health and protecting against arthritis, amongst other benefits:

* Decrease in the systemic risk factors for cardiovascular disease (glucose levels, blood pressure, plasma lipid levels).
* Alteration in the sympathetic nervous system, as well as the neuroendocrine system in lab animals and, sometimes, humans.
* Reduction in oxidative damage due to a decreased production of Reactive Oxygen Species (ROS).
* Increase in CoQ-dependent reductases within the plasma membrane, thus protecting phospholipids and preventing the lipid peroxidation reaction progression.
* Inhibition of mTOR pathway and consequent induction of a[[Autophagy|utophagy]], a specific process that recycles cellular waste.
* Activation of known pro-longevity pathways such as FOXO/AMPK/SIRT, which are evolutionarily conserved across various species.

== Controversies of calorie restriction research ==
There are several criticisms against CR, some of which are highlighted by Sohal and Forster (2014) in “''Caloric Restriction and the Aging Process: A Critique''”.<ref>Sohal, R. S., & Forster, M. J. (2014). Caloric restriction and the aging process: a critique. ''Free radical biology & medicine'', ''73'', 366–382. <nowiki>https://doi.org/10.1016/j.freeradbiomed.2014.05.015</nowiki></ref> The authors highlight that there is a large disparity in CR-related longevity increases: namely, that longevity effects are not universal and sometimes are not shared by different genetic strains of the same species. Moreover, the control animals in the widely-cited caloric restriction studies were fed ''ad libitum'', causing them to become overweight and vulnerable to disease and early deaths. Therefore the relative benefit in the CR group was exaggerated compared to control subjects. In other words, animals with CR diets appear to live relatively longer because the control animals were dying from complications of excess feeding.

Another challenge related to CR as an effective intervention for human aging is the difficulty in compliance over long periods of time.<ref name=":0" /> Concerns over mental and sexual health have also been raised with more severe CR. There are concerns over the loss of weight and fat mass in younger people practicing CR. Exercising along with CR and good nutrition (high protein diet) appears to be highly beneficial for loss of free fat.<ref name=":0" /> New nutritional approaches such as intermittent fasting have emerged. However, there is comparatively limited research on the topic, with CR being the most well-studied nutritional intervention for healthy aging. Furthermore, worms that were treated with Allantoin, rapamycin, TSA, and LY-294002 had a reduced decline in pharyngeal pumping, which indicates a slower rate of aging. Thus, the study uncovered that not only could drug treatments increase longevity but they could also improve the organism’s healthfulness.

It is important to note that researchers are growingly becoming aware that CR or strict intermittent fasting is not a “one size fits all”, but rather an efficient strategy for certain individuals in specific metabolic contexts. For instance, some studies have shown that two people's glucose responses are significantly different even after eating the same food.<ref>Zeevi, D., Korem, T., Zmora, N., Israeli, D., Rothschild, D., & Weinberger, A. et al. (2015). Personalized Nutrition by Prediction of Glycemic Responses. ''Cell'', ''163''(5), 1079-1094. doi: 10.1016/j.cell.2015.11.001</ref> Supporting these findings, companies like [https://www.lumen.me/metabolic-flexibility Lumen Metabolism] and [https://www.levelshealth.com Levels] are offering personalised dietary recommendations based on the measurement of an individuals’s [[metabolic flexibility]].

Similar to non-human primates, the effects of CR on lifespan remain controversial in humans. However, what seems clear from obesity studies is that eating too much results in poor health and decreased longevity.<ref>Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., Chahory, S., Cordonnier, N., Desquilbet, L., Hurion, M. and Zahariev, A., 2018. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. ''Communications biology'', ''1''(1), pp.1-8.</ref>
<references />
[[Category:Longevity]]

Autophagy

2022-06-29T20:31:21Z

SchmauckMedina: Added the Mitophagy section and a paragraph with some of the subtypes of mitophagy.

Autophagy (“''auto''” meaning “self”, and “''phagy''” meaning “to eat”) is a catabolic process highly conserved in eukaryotes, in which cytoplasmic components are delivered to the lysosome and degraded. It is a key process for the regulation of cellular energetic equilibrium and plays a housekeeping role by removing cellular waste, damaged organelles, aggregated or misfolded proteins and even intracellular pathogens<ref name=":0" /><ref>Glick, D., Barth, S., & Macleod, K. (2010). Autophagy: cellular and molecular mechanisms. ''The Journal Of Pathology'', ''221''(1), 3-12. doi: 10.1002/path.2697</ref>. The process of autophagy is also critical in several developmental processes and in response to nutrient stresses<ref>Maria Fimia, G., Stoykova, A., Romagnoli, A., Giunta, L., Di Bartolomeo, S., & Nardacci, R. et al. (2007). Ambra1 regulates autophagy and development of the nervous system. ''Nature'', ''447''(7148), 1121-1125. doi: 10.1038/nature05925</ref><ref>Qu, X., Zou, Z., Sun, Q., Luby-Phelps, K., Cheng, P., & Hogan, R. et al. (2007). Autophagy Gene-Dependent Clearance of Apoptotic Cells during Embryonic Development. ''Cell'', ''128''(5), 931-946. doi: 10.1016/j.cell.2006.12.044</ref>. The connections between dysfunctional autophagy with aging and age-related diseases are abundant<ref name=":0">Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK, Bjedov I, Palikaras K, Simonsen A, Johansen T, Tavernarakis N, Rubinsztein DC, Partridge L, Kroemer G, Labbadia J, Fang EF. Autophagy in healthy aging and disease. Nat Aging. 2021 Aug;1(8):634-650. doi: 10.1038/s43587-021-00098-4. Epub 2021 Aug 12. PMID: 34901876; PMCID: PMC8659158.</ref>.

There are three well defined types of autophagy: macro-autophagy, micro-autophagy and chaperone-mediated autophagy<ref>Parzych, K., & Klionsky, D. (2014). An Overview of Autophagy: Morphology, Mechanism, and Regulation. ''Antioxidants &Amp; Redox Signaling'', ''20''(3), 460-473. doi: 10.1089/ars.2013.5371</ref>, with chaperone-assisted selective autophagy (CASA) being recently added<ref>Ulbricht A, Gehlert S, Leciejewski B, Schiffer T, Bloch W, Höhfeld J. Induction and adaptation of chaperone-assisted selective autophagy CASA in response to resistance exercise in human skeletal muscle. Autophagy. 2015;11(3):538-46. doi: 10.1080/15548627.2015.1017186. PMID: 25714469; PMCID: PMC4502687.</ref><ref>Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Fürst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Höhfeld J. Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol. 2010 Jan 26;20(2):143-8. doi: 10.1016/j.cub.2009.11.022. Epub 2010 Jan 7. PMID: 20060297.</ref>. Despite differences in their mechanism of degradation and the molecular components they require, all three types of autophagy share in common the delivery of cytoplasmic cargo to the lysosome for proteolytic degradation. Due to its role in disease, macro-autophagy in particular has been the main focus of research over the past few decades, and often the term “autophagy” is used to refer to the macro-autophagy type of autophagy.

==== Mitophagy ====
The selective degradation of Mitochondria through autophagy is known as mitophagy. There are multiple sub-types of mitophagy, such as PINK1/Parkin-dependant, Ubiquitin-independent receptor-mediated and others like piecemeal mitophagy<ref>Bakula D, Scheibye-Knudsen M. MitophAging: Mitophagy in Aging and Disease. Front Cell Dev Biol. 2020 Apr 15;8:239. doi: 10.3389/fcell.2020.00239. PMID: 32373609; PMCID: PMC7179682.</ref>.<references />
[[Category:Longevity]]

Autophagy

2022-06-29T19:38:03Z

SchmauckMedina: Word "recently" added in the CASA section.

Autophagy (“''auto''” meaning “self”, and “''phagy''” meaning “to eat”) is a catabolic process highly conserved in eukaryotes, in which cytoplasmic components are delivered to the lysosome and degraded. It is a key process for the regulation of cellular energetic equilibrium and plays a housekeeping role by removing cellular waste, damaged organelles, aggregated or misfolded proteins and even intracellular pathogens<ref>Glick, D., Barth, S., & Macleod, K. (2010). Autophagy: cellular and molecular mechanisms. ''The Journal Of Pathology'', ''221''(1), 3-12. doi: 10.1002/path.2697</ref>. The process of autophagy is also critical in several developmental processes and in response to nutrient stresses<ref>Maria Fimia, G., Stoykova, A., Romagnoli, A., Giunta, L., Di Bartolomeo, S., & Nardacci, R. et al. (2007). Ambra1 regulates autophagy and development of the nervous system. ''Nature'', ''447''(7148), 1121-1125. doi: 10.1038/nature05925</ref><ref>Qu, X., Zou, Z., Sun, Q., Luby-Phelps, K., Cheng, P., & Hogan, R. et al. (2007). Autophagy Gene-Dependent Clearance of Apoptotic Cells during Embryonic Development. ''Cell'', ''128''(5), 931-946. doi: 10.1016/j.cell.2006.12.044</ref>. The connections between dysfunctional autophagy with aging and age-related diseases are abundant<ref>Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK, Bjedov I, Palikaras K, Simonsen A, Johansen T, Tavernarakis N, Rubinsztein DC, Partridge L, Kroemer G, Labbadia J, Fang EF. Autophagy in healthy aging and disease. Nat Aging. 2021 Aug;1(8):634-650. doi: 10.1038/s43587-021-00098-4. Epub 2021 Aug 12. PMID: 34901876; PMCID: PMC8659158.</ref>.

There are three well defined types of autophagy: macro-autophagy, micro-autophagy and chaperone-mediated autophagy<ref>Parzych, K., & Klionsky, D. (2014). An Overview of Autophagy: Morphology, Mechanism, and Regulation. ''Antioxidants &Amp; Redox Signaling'', ''20''(3), 460-473. doi: 10.1089/ars.2013.5371</ref>, with chaperone-assisted selective autophagy (CASA) being recently added<ref>Ulbricht A, Gehlert S, Leciejewski B, Schiffer T, Bloch W, Höhfeld J. Induction and adaptation of chaperone-assisted selective autophagy CASA in response to resistance exercise in human skeletal muscle. Autophagy. 2015;11(3):538-46. doi: 10.1080/15548627.2015.1017186. PMID: 25714469; PMCID: PMC4502687.</ref><ref>Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Fürst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Höhfeld J. Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol. 2010 Jan 26;20(2):143-8. doi: 10.1016/j.cub.2009.11.022. Epub 2010 Jan 7. PMID: 20060297.</ref>. Despite differences in their mechanism of degradation and the molecular components they require, all three types of autophagy share in common the delivery of cytoplasmic cargo to the lysosome for proteolytic degradation. Due to its role in disease, macro-autophagy in particular has been the main focus of research over the past few decades, and often the term “autophagy” is used to refer to the macro-autophagy type of autophagy.
<references />
[[Category:Longevity]]

Autophagy

2022-06-29T19:36:54Z

SchmauckMedina: CASA system was added.

Autophagy (“''auto''” meaning “self”, and “''phagy''” meaning “to eat”) is a catabolic process highly conserved in eukaryotes, in which cytoplasmic components are delivered to the lysosome and degraded. It is a key process for the regulation of cellular energetic equilibrium and plays a housekeeping role by removing cellular waste, damaged organelles, aggregated or misfolded proteins and even intracellular pathogens<ref>Glick, D., Barth, S., & Macleod, K. (2010). Autophagy: cellular and molecular mechanisms. ''The Journal Of Pathology'', ''221''(1), 3-12. doi: 10.1002/path.2697</ref>. The process of autophagy is also critical in several developmental processes and in response to nutrient stresses<ref>Maria Fimia, G., Stoykova, A., Romagnoli, A., Giunta, L., Di Bartolomeo, S., & Nardacci, R. et al. (2007). Ambra1 regulates autophagy and development of the nervous system. ''Nature'', ''447''(7148), 1121-1125. doi: 10.1038/nature05925</ref><ref>Qu, X., Zou, Z., Sun, Q., Luby-Phelps, K., Cheng, P., & Hogan, R. et al. (2007). Autophagy Gene-Dependent Clearance of Apoptotic Cells during Embryonic Development. ''Cell'', ''128''(5), 931-946. doi: 10.1016/j.cell.2006.12.044</ref>. The connections between dysfunctional autophagy with aging and age-related diseases are abundant<ref>Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK, Bjedov I, Palikaras K, Simonsen A, Johansen T, Tavernarakis N, Rubinsztein DC, Partridge L, Kroemer G, Labbadia J, Fang EF. Autophagy in healthy aging and disease. Nat Aging. 2021 Aug;1(8):634-650. doi: 10.1038/s43587-021-00098-4. Epub 2021 Aug 12. PMID: 34901876; PMCID: PMC8659158.</ref>.

There are three well defined types of autophagy: macro-autophagy, micro-autophagy and chaperone-mediated autophagy<ref>Parzych, K., & Klionsky, D. (2014). An Overview of Autophagy: Morphology, Mechanism, and Regulation. ''Antioxidants &Amp; Redox Signaling'', ''20''(3), 460-473. doi: 10.1089/ars.2013.5371</ref>, with chaperone-assisted selective autophagy (CASA) being added<ref>Ulbricht A, Gehlert S, Leciejewski B, Schiffer T, Bloch W, Höhfeld J. Induction and adaptation of chaperone-assisted selective autophagy CASA in response to resistance exercise in human skeletal muscle. Autophagy. 2015;11(3):538-46. doi: 10.1080/15548627.2015.1017186. PMID: 25714469; PMCID: PMC4502687.</ref><ref>Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Fürst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Höhfeld J. Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol. 2010 Jan 26;20(2):143-8. doi: 10.1016/j.cub.2009.11.022. Epub 2010 Jan 7. PMID: 20060297.</ref>. Despite differences in their mechanism of degradation and the molecular components they require, all three types of autophagy share in common the delivery of cytoplasmic cargo to the lysosome for proteolytic degradation. Due to its role in disease, macro-autophagy in particular has been the main focus of research over the past few decades, and often the term “autophagy” is used to refer to the macro-autophagy type of autophagy.
<references />
[[Category:Longevity]]

Aging and neurodegeneration

2022-06-29T17:04:29Z

SchmauckMedina: I did 5 grammatical corrections. Hyperlinked the word NAD+. Added 6 unique references. Added around 150 words. Added a new section called "Induction of Autophagy". Demanded 1 citation in the section of "Supplementing NAD+".

[[File:Prevalence of neurodegenerative disease in older individuals.jpg|thumb|485x485px|The prevalence of neurodegenerative diseases increases exponentially in older age. a) The prevalence of Alzheimer's disease per 1000 men and women. b) The prevalence of Parkinson's diseases per 100,000 men and women. 2014 US Data.<ref>Mehta, P., Kaye, W., Raymond, J., Wu, R., Larson, T., Punjani, R., Heller, D., Cohen, J., Peters, T., Muravov, O., & Horton, K. (2018). Prevalence of Amyotrophic Lateral Sclerosis - United States, 2014. ''MMWR. Morbidity and mortality weekly report'', ''67''(7), 216–218. <nowiki>https://doi.org/10.15585/mmwr.mm6707a3</nowiki></ref>]]Aging is the major risk factor for most neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.<ref name=":0">Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019). Ageing as a risk factor for neurodegenerative disease. ''Nature Reviews Neurology'', ''15''(10), 565-581. https://www.nature.com/articles/s41582-019-0244-7</ref> The most common types of neurodegenerative diseases primarily occur in older individuals. In fact, 1 in 10 individuals over 65 years old is expected to suffer a neurodegenerative condition, with that likelihood increasing exponentially with age.<ref name=":0" />

Neurodegenerative diseases of the central nervous system (CNS) are defined by the progressive and irreversible loss of neuronal cells and is associated to behavioral impairment, including loss of motor and/or cognitive functions.<ref>Mayne, K., White, J., McMurran, C., Rivera, F., & de la Fuente, A. (2020). Aging and Neurodegenerative Disease: Is the Adaptive Immune System a Friend or Foe?. ''Frontiers In Aging Neuroscience'', ''12''. doi: 10.3389/fnagi.2020.572090</ref>

Given the strong link between neurodegenerative diseases and aging, neurodegeneration is often considered as part of the aging process in the brain.<ref name=":0" />

Very few or no effective treatments are available for neurodegenerative conditions, and most are focused on alleviating the symptoms rather than targeting the root of the disease. Therefore, addressing the brain's aging process directly to slow its progression may offer a better strategy to mitigate the onset and burden of neurodegenerative diseases.

==Risk factors for neurodegenerative diseases==
[[File:Aging as a risk factor for Alzheimer's disease.jpg|thumb|421x421px|A comparison of aging versus other risk factors for Alzheimer’s disease. The risk of Alzheimer’s disease increases approximately 100-fold between the ages of 50 and 75. The combined increase in the risk of Alzheimer’s from genetics (ApoE ε4/ε4), sex (female), hypertension, smoking, physical inactivity, and diabetes is approximately 10-fold. Data extracted from the CDC. <ref name=":1">Matt Kaeberlein, PhD, Time for a New Strategy in the War on Alzheimer’s Disease, ''Public Policy & Aging Report'', Volume 29, Issue 4, 2019, Pages 119–122, <nowiki>https://doi.org/10.1093/ppar/prz020</nowiki></ref>]]
There are a number of risk factors for neurodegenerative diseases.

===Aging===

Aging is the most significant risk factor for several neurodegenerative diseases. Over the age of 65, over 10% of individuals are reported to have Alzheimer's disease, and the prevalence continues to increase with age. By the age of 95, over 50% of individuals are estimated to have Alzheimer's disease in the USA.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181909/ Qiu, C., Kivipelto, M., & von Strauss, E. (2009). Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. ''Dialogues in clinical neuroscience'', ''11''(2), 111.]</ref>

The increased risk of Alzheimer's disease due to aging is over 100-fold, whereas other major risk factors (genetics, environmental and developmental factors) combined are approximately 10-fold. <ref name=":1" />

===Genetic risk factors===
In most common neurodegenerative diseases, there are known genetic risk factors that explain to varying degrees the onset and advance of neurodegeneration. Some neurodegenerative diseases are monogenic, meaning they are mediated exclusively by the dysfunction of a single gene, as is the case of Huntington's disease (which is caused by an abnormal repeat expansion of the Huntingtin ''HTT'' gene). However, most neurodegenerative diseases including Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS) or Parkinson's disease, display a complex genetic relationship and are associated to a plethora of genetic markers, each contributing with a small effect size to the disease phenotype.<ref>Manzoni, C., Lewis, P., & Ferrari, R. (2020). Network Analysis for Complex Neurodegenerative Diseases. ''Current Genetic Medicine Reports'', ''8''(1), 17-25. doi: 10.1007/s40142-020-00181-z</ref>

For Alzheimer's disease and Parkinson's disease, genetic variants with high penetrance have identified β-amyloid and α-synuclein production in the pathogenesis, respectively. Variants with high penetrance often lead to familial forms of the disease, which are characterised for early onset and low prevalence in the population, accounting for less than 1% of cases in Alzheimer's disease. <ref>Raimundo, R., Jesus, R., & Veiga, A. (2021). Familial Alzheimer’s Disease due to Presenilin 1 Mutation at the Age of 33: a Case Report. ''SN Comprehensive Clinical Medicine'', ''3''(10), 2021-2023. doi: 10.1007/s42399-021-00982-5</ref> Familial cases have nonetheless been subject to considerable research interest, hoping to identify common disease mechanisms.<ref>Gan, L., Cookson, M.R., Petrucelli, L. ''et al.'' Converging pathways in neurodegeneration, from genetics to mechanisms. ''Nat Neurosci'' 21, 1300–1309 (2018). <nowiki>https://doi.org/10.1038/s41593-018-0237-7</nowiki></ref>

In sporadic forms of the disease (occurring with no discernible pattern), Genome-Wide Association Studies (GWAS) have been able to identify important risk-alleles, such as mutations in the ''APOE'' gene for Alzheimer's disease, or mutations in the ''SNCA'' and ''MAPT'' genes for Parkinson's. Mutations associated with Alzheimer's disease and Parkinson's disease do not seem to overlap to a significant degree.<ref>Moskvina V, Harold D, Russo G, et al. Analysis of Genome-Wide Association Studies of Alzheimer Disease and of Parkinson Disease to Determine If These 2 Diseases Share a Common Genetic Risk. ''JAMA Neurol.'' 2013;70(10):1268–1276. doi:10.1001/jamaneurol.2013.448</ref>

Polymorphisms in the ''APOE'' gene, a gene which encodes a protein mainly involved in lipid metabolism, is the best-described genetic factor for Alzheimer's disease. ''APOE'' has three major variants, ε2, ε3 and ε4. Whilst the ε2 allele confers a reduced risk for Alzheimer's disease (0.56-fold risk for heterozygous and homozygous carriers) compared to the most common ε3 allele, ε4 has shown to be a major risk factor for Alzheimer's disease (3.63-fold risk for heterozygous carriers and 14.49-fold for homozygous carriers).<ref>Yamazaki, Y., Zhao, N., Caulfield, T.R. ''et al.'' Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. ''Nat Rev Neurol'' 15, 501–518 (2019). <nowiki>https://doi.org/10.1038/s41582-019-0228-7</nowiki></ref>

===Environmental Toxins===
Long-term exposure to environmental toxins has been described as a risk factor for various neurodegenerative diseases.<ref name=":2" /> Environmental toxins most commonly refers to metals toxins (such as zinc, copper or mercury) and biotoxins, which are toxic substances of a biological origin (bacteria, plants or fungi).

Environmental toxins have been shown to play a role in inducing oxidative stress and up-regulating pro-inflammatory cytokines, which can result in increased inflammatory responses and neuronal damage.<ref name=":2" /> Some studies have found that metal toxins and biotoxins interact together in a complex manner, and that the nature of this relationship can determine the degree of impairment in neurological function.<ref>Kamel, F., & Hoppin, J. A. (2004). Association of pesticide exposure with neurologic dysfunction and disease. ''Environmental health perspectives'', ''112''(9), 950–958. <nowiki>https://doi.org/10.1289/ehp.7135</nowiki></ref>

Chronic exposure to environmental toxins has been directly implicated in amyloid-β aggregation and τ-hyperphosphorylation, two pathological traits that lead to the formation of amyloid plaques and neurofibrillary tangles characteristic of Alzheimer's disease.<ref name=":2">Maryam Vasefi, Ehsan Ghaboolian-Zare, Hamzah Abedelwahab, Anthony Osu, Environmental toxins and Alzheimer's disease progression, Neurochemistry International, Volume 141, 2020, ISSN 0197-0186, <nowiki>https://doi.org/10.1016/j.neuint.2020.104852</nowiki>.</ref><ref>Plamena R. Angelova, Sources and triggers of oxidative damage in neurodegeneration, Free Radical Biology and Medicine, Volume 173, 2021, Pages 52-63, ISSN 0891-5849, <nowiki>https://doi.org/10.1016/j.freeradbiomed.2021.07.003</nowiki>.</ref>. Moreover, fetal and even epigenetic mechanisms (before pregnancy) to due maternal exposure to such toxins has been proposed to be the underlying cause of the phenotypic diversity and likelihood in developing neurodegenerative diseases.<ref>Chin-Chan, M., Navarro-Yepes, J., & Quintanilla-Vega, B. (2015). Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. ''Frontiers In Cellular Neuroscience'', ''9''. doi: 10.3389/fncel.2015.00124</ref>

=====How to reduce the risk of exposure to environmental toxins?=====
Human activity has led to increased levels of environmental toxins that can be harmful to humans and other species. Whilst avoiding heavy metals and other toxins in our daily lives might prove to be challenging, health experts have proposed a number of habits to reduce the risk of exposure to environmental toxins.<ref>https://www.miskawaanhealth.com/heavy-metal-contamination/</ref>

These habits include but are not limited to:

*Avoiding the use of pesticides whenever possible. This includes direct exposure to pesticides as well as the preferential consumption of organic food, given that chemical-synthetic pesticides are banned in organic farming.
* Handling wild mushrooms properly before consumption. The outer peel of mushrooms, specially those grown near industrial areas, has been shown to accumulate high levels of heavy metals.<ref>Spencer, P., & Palmer, V. (2021). Direct and Indirect Neurotoxic Potential of Metal/Metalloids in Plants and Fungi Used for Food, Dietary Supplements, and Herbal Medicine. ''Toxics'', ''9''(3), 57. doi: 10.3390/toxics9030057</ref>
*Avoiding products contained in aluminium cans (such as beverages, deodorants and other cosmetic products).
*Eating seafood with moderation. Despite the fact that consumption of fish and seafood is associated to a reduced risk of cardiovascular disease, a moderate consumption is advised. High mercury levels are observed amongst high-end fish and seafood consumers and it can be particularly dangerous for pregnant women.<ref>Schaefer, Zoffer, Yrastorza, Pearlman, Bossart, Stoessel, & Reif. (2019). Mercury Exposure, Fish Consumption, and Perceived Risk among Pregnant Women in Coastal Florida. ''International Journal Of Environmental Research And Public Health'', ''16''(24), 4903. doi: 10.3390/ijerph16244903</ref>

===Head Trauma===
Head trauma is a risk factor for a variety of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), FrontoTemporal Dementia (FTD) and chronic traumatic encephalopathy and raises the risk of all-cause dementia by a factor of approximately 1.5.<ref>Li Y, Li Y, Li X, Zhang S, Zhao J, Zhu X, et al. (2017) Head Injury as a Risk Factor for Dementia and Alzheimer’s Disease: A Systematic Review and Meta-Analysis of 32 Observational Studies. PLoS ONE 12(1): e0169650. <nowiki>https://doi.org/10.1371/journal.pone.0169650</nowiki></ref> Head trauma has been associated with defects in the blood-brain barrier, neuroinflammation, τ-hyperphosphorylation and TDP-43 aggregation.<ref>Graham NS, Sharp DJ, Understanding neurodegeneration after traumatic brain injury: from mechanisms to clinical trials in dementia. ''Journal of Neurology, Neurosurgery & Psychiatry'' 2019;'''90:'''1221-1233.</ref>

===Social Environmental Factors===
Social environmental conditions during childhood have been suggested as a risk factor for neurodegenerative diseases. Lower socioeconomic status during early life and childhood trauma appears to be associated with decreased late-life cognitive abilities, but does not directly influence the risk of Alzheimer's disease or the rate of cognitive decline.<ref>Wilson RS, Scherr PA, Hoganson G, Bienias JL, Evans DA, Bennett DA. Early life socioeconomic status and late life risk of Alzheimer's disease. Neuroepidemiology. 2005;25(1):8-14. doi: 10.1159/000085307. </ref>

Lower education levels and lower general cognitive abilities in childhood are associated to a higher risk of developing Alzheimer's disease and to a lower cognitive reserve .<ref>Stern, Yaakov, Cognitive reserve in ageing and Alzheimer's disease, The Lancet Neurology, Volume 11, Issue 11, 1006 - 1012, <nowiki>https://doi.org/10.1016/S1474-4422(12)70191-6</nowiki></ref><ref>Mehta, K.M., Stewart, A.L., Langa, K.M., Yaffe, K., Moody-Ayers, S., Williams, B.A. and Covinsky, K.E. (2009), “Below average” self-assessed school performance and Alzheimer's disease in the Aging, Demographics, and Memory Study. Alzheimer's & Dementia, 5: 380-387. <nowiki>https://doi.org/10.1016/j.jalz.2009.07.039</nowiki></ref> Cognitive reserve (CR) is defined as the resilience that individuals display in terms of behavioural function when there is existing brain damage. Individuals with higher CR will showcase a lesser degree of impairment than individuals with lower CR, when both are subject to the same degree of observable brain damage. In other words, individuals with a higher cognitive reserve are likely to remain functional for longer. Higher levels of education and cognitively complex occupations are associated to a higher CR and seem to be protective against the onset of Alzheimer's disease.<ref>Staff, R., Murray, A., Deary, I., & Whalley, L. (2004). What provides cerebral reserve?. ''Brain'', ''127''(5), 1191-1199. doi: 10.1093/brain/awh144</ref>

==Brain aging and functional decline ==
The brain tissue of older adults is associated to the build-up of protein deposits such as tau protein and amyloid-β.

===The Hallmarks of Aging ===
''See the full article on the [[Hallmarks of Aging]].''[[File:The nine hallmarks of brain aging..jpg|thumb|552x552px|The ten hallmarks of brain aging are involved in many neurodegenerative diseases. These include Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), ataxia telangiectasia (AT), Huntington disease (HD) and Parkinson disease (PD).<ref name=":3">Mattson, M., & Arumugam, T. (2018). Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. ''Cell Metabolism'', ''27''(6), 1176-1199. doi: 10.1016/j.cmet.2018.05.011</ref>]]
The basic process of neurodegeneration appears to be fundamentally connected to the hallmarks of aging.

The nine so-called '[[Hallmarks of Aging|"Hallmarks of Aging"]] were defined in 2013 by Lopez-Otin et al.<ref name=":4">López-Otín, C., Blasco, M., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. ''Cell'', ''153''(6), 1194-1217. doi: 10.1016/j.cell.2013.05.039</ref> and represent the basic biological processes underlying aging at the organismal level. These hallmarks are now widely used in the aging field and in the context of neurodegenerative diseases.

The hallmarks are: genomic instability, epigenetic alterations, telomere attrition, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication. These hallmarks correlate with risk to neurodegenerative diseases.<ref name=":0" />

Importantly, these hallmarks just offer a phenotypic observation of features associated with aging, but fail to provide a definitive ''causal'' explanation to the aging process.

===The Hallmarks of Brain Aging===
Inspired by the original "[[Hallmarks of Aging]]", researchers have attempted to characterise the aging process more specifically in the nervous tissue. A study in 2018 named the "Hallmarks of Brain Aging" revealed that aging of the brain, at the cellular and molecular levels, resembles to a large degree the hallmarks of aging at the whole organism level.<ref name=":3" /><ref name=":4" />

Some reported differences between aging of the brain and other tissues are telomere attrition and cellular senescence.<ref name=":3" /> These hallmarks have not been observed in neurons, and it remains to be established whether they occur in other brain cell types such as glial cells. One hypothesis is that differences might arise from the nature of the brain as a non-proliferative, post-mitotic tissue.

The proposed "Hallmarks of Brain Aging" are ten: mitochondrial dysfunction, accumulation of oxidatively damaged molecules, impaired lysosome and proteasome function, dysregulation of neuronal calcium homeostasis, compromised adaptive cellular stress responses, aberrant neuronal network activity, impaired DNA repair, inflammation, stem ell exhaustion and dysregulated energy metabolism.

Below we discuss the original "Hallmarks of Aging" with a focus on neurodegenerative disease:<ref name=":0" /><ref name=":3" /><ref name=":4" />

===1. Mitochondrial Dysfunction===
''See the full article on [[Mitochondrial Dysfunction|mitochondrial dysfunction]].''

Neurons are metabolically highly active cells that pose high energy demands. [[Mitochondria]] play a key role in energy production, but become impaired in brain aging and neurodegenerative diseases. The production of reactive oxygen species (ROS) is associated with aging and neurodegeneration.

Mitophagy is the process that results in the selective degradation of [[mitochondria]]. Growing evidence suggests that defects in mitophagy occurring in aging contribute to the neurodegenerative process. Studies have demonstrated that DNA damage in the cell can contribute to [[Mitochondrial Dysfunction|mitochondrial dysfunction]]. Therefore, inducing mitophagy has been suggested as a potential strategy to mitigate brain aging.

===2. '''Impaired DNA Repair:''' ===
Healthy, young cells are able to clear damaged DNA and rapidly repair it through several mechanisms. However, analysis of brain tissue from old individuals have revealed both increased amounts of damaged DNA as well as decreased expression of DNA repair proteins, suggesting DNA repair mechanisms become increasingly dysfunctional with age.<ref name=":3" /> Impairment of DNA repair pathways is also sufficient to cause accelerated aging phenotypes, as seen in patients with diseases such as the Werner syndrome.<ref>Scheibye-Knudsen M. Neurodegeneration in accelerated aging. ''Dan Med J.'' 2016;63:1–10.</ref>

Several types of DNA damage are associated with neurodegeneration.<ref name=":0" /> Disruptive molecules known as reactive oxygen species (ROS) can induce DNA damage and are associated with aging and neurodegenerative disease. Intracellular accumulation of proteins, nucleic acids, and lipids with signs of oxidative damage are seen in neurons. DNA damage itself can lead to genomic instability and cause an increase in cellular senescence and inflammation, which accelerate brain aging. Additionally, ongoing damage to DNA induces activation of a protein called PARP1 which results in depletion of NAD+, an essential co-factor for sirtuin enzymes with important roles in healtspan.

===3. '''Telomere Attrition'''===
''See the full article on [[Telomeres]].''

[[Telomeres]] are the protective 'caps' on the end of chromosomes and are composed of protein and DNA. Each time a cell divides, the telomeres generally become shorter. The shortening of telomeres occurs as part of biological aging and leads to cellular senescence. It is associated with neurodegeneration and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.

As discussed previously, telomeres of post-mitotic tissues such as the nervous system do not shorten.<ref name=":3" /> However, during neurogenesis, newly generated neutrons after differentiation from neural stem cells are highly sensitive to telomere damage and can become apoptotic.<ref>Cheng A, Shinya K, Wan R, Tang SC, Miura T, Tang H, Khatri R, Gleichman M, Ouyang X, Liu D, et al. Telomere protection mechanisms change during neurogenesis and neuronal maturation: newly generated neurons are hypersensitive to telomere and DNA damage. ''J Neurosci.'' 2007;27:3722–3733. </ref>

===4. '''Cellular Senescence'''===
''See the full article on [[Cellular senescence]].''

Cellular senescence refers to a particular state: cells have stopped dividing and growing in size, become resistant to apoptosis, begin releasing pro-inflammatory factors and express the proteins p21 and p16.<ref>Childs BG, Baker DJ, Kirkland JL, Campisi J, van Deursen JM. Senescence and apoptosis: dueling or complementary cell fates? ''EMBO Rep.'' 2014;15:1139–1153.</ref> Cellular senescence can occur as a result of DNA damage to the cell. With age, the number of senescent neurons increases in the brain.

Similarly to the case of telomere attrition, neurons do not seem to undergo senescence.<ref name=":3" /> However, evidence is contradictory as studies in old mice have proposed that up to 40% of cortical, hippocampal and peripheral neurons might be senescent.<ref name=":0" /> Cellular senescence has also been linked with exacerbated age-related brain dysfunction. As such, targeting senescent cells is being considered as a therapeutic strategy for patients with neurodegenerative diseases.

===5. '''Stem Cell Exhaustion'''===
Stem cells are required for the creation of new cells in later life. Stem cell function appears to decline over an organism's lifespan and has been linked to several hallmarks such as DNA damage, defective proteostasis and epigenetic deregulation. The loss of stem cells is also associated to age-related neurodegeneration.<ref name=":0" />

New neurons can be generated from neuronal stem cells during adulthood in a process known as neurogenesis.<ref>Ming GL, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. ''Neuron.'' 2011;70:687–702.</ref> This process is specially important in the hippocampus and the olfactory bulb for maintaining functional learning and memory processes, and it has been shown to decline durning normal aging.<ref>Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, van Praag H. When neurogenesis encounters aging and disease. ''Trends Neurosci.'' 2010;33:569–579.</ref>

=== 6. '''Loss of Proteostasis'''===
Proteostasis refers to the balance of protein production and degradation in cells and tissues. A balance of proteins is crucial for the normal functioning of cells. The misfolding, aggregation or deposition of proteins has been shown to be connected to several neurodegenerative disorders.

Impaired cellular “waste disposal” and recycling mechanisms, including autophagy, lysosomal function and the proteasome machinery has been shown to decline in neurons during aging.<ref name=":3" /> Intact proteosomal machinery is particularly important for the nervous tissue. For instance, mutations in the proteosomal machinery are sufficient to cause early-onset Parkinson’s disease due to the inability to degrade α-synuclein in the brain.<ref>Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, Mizuno Y, Kosik KS, Selkoe DJ. Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson’s disease. ''Science.'' 2001;293:263–269.</ref>

===7. '''Epigenetic Alterations'''===
Epigenetics describe reversible, heritable changes to the function of genes that do not involve changes to the DNA code itself. These gene modifications include methylation, by which a methyl group is added to a DNA molecule, histone modifications or non-protein-coding-RNAs. Epigenetic changes have been associated with neurodegenerative diseases.<ref name=":0" />

Nutrition is one well-studied epigenetic regulator that can have profound effects in disease and in age-related cognitive decline. Calorie restriction and other environmental factors like exercise or stress management, which generate changes in the epigenome, have been proposed as novel approaches to prevent neurodegenerative diseases.<ref>Dauncey MJ. Nutrition, the brain and cognitive decline: insights from epigenetics. ''Eur J Clin Nutr.'' 2014; 68:1179–1185.</ref>

===8. '''Altered Intercellular Communication'''===
Changes to levels of hormones such as insulin, IGF1 or leptin occur with age and are linked with neurodegeneration. In addition, loss of regulation of the immune system with age is implicated in neurodegenerative diseases. For example, inflammation, a protective response to injury, becomes chronically upregulated with age and high levels of inflammation are related to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.<ref name=":0" />

Given the interconnectedness between the brain and immune function, it has been hypothesised that a decline in immune responses in the brain is an important factor in neurodegenerative diseases.<ref>Amor, S. & Woodroofe, M. N. Innate and adaptive immune responses in neurodegeneration and repair. ''Immunology.'' 2014; '''141''', 287–291.</ref> A key process of the immune response is inflammation. Chronic inflammation leads to activation of microglia and pro-inflammatory cytokines as well as increased oxidative stress, all earmarks associated to neurodegenerative diseases.<ref>Currais, A. Ageing and inflammation – a central role for mitochondria in brain health and disease. ''Ageing Res. Rev. 2025;'' '''21''', 30–42.</ref>

===9. Dysregulated Energy Metabolism===
''See the full article on [[Metabolic flexibility]].''

Several nutrient sensing biochemical pathways are linked to aging and longevity. These include insulin-like growth factor 1 (IGF1), mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK) and the sirtuin enzymes. Studies in mice, worm and fly species have demonstrated that modulating these pathways can extend lifespan. Metabolic dysfunction in these pathways is commonly associated with neurological, age-related diseases.<ref name=":0" />

Neurons are continuously subject to high bioenergetic demands. The brain is, in fact, the most energy-consuming organ and is responsible for 20% of the total energy use of an organism at rest, despite only accounting for 2% of the human bodyweight. During aging, neural networks are highly susceptible to perturbation due to dysregulated energy metabolism and can become pathological.<ref name=":3" /> For instance, excitatory and inhibitory neural network imbalances can result during aging as a result of aging-related impaired GABAergic signalling.<ref>Heise KF, Zimerman M, Hoppe J, Gerloff C, Wegscheider K, Hummel FC. The aging motor system as a model for plastic changes of GABA-mediated intracortical inhibition and their behavioral relevance. J Neurosci. 2013;33:9039–9049.</ref>

==Interconnectedness of the hallmarks==
The hallmarks of aging are highly interconnected and occur in a complex process that is part of neurodegeneration. For example, the loss of proteostasis is strongly linked to inflammation and senescence. The metabolic dysfunction that occurs with age and is present in neurodegenerative diseases is associated with mitochondrial dysfunction and oxidative stress. The reduction in number of stem cells is linked to almost all other hallmarks, such as genomic instability, epigenetic alterations, mitochondrial dysfunction, cellular senescence and telomere attrition.<ref name=":0" />
==Aging and Alzheimer's disease==

==New treatments for neurodegenerative diseases==
Current efforts to develop evidence-based treatments for neurodegenerative diseases are ongoing, but no highly effective treatment approaches have been discovered. Given the complexity of age-related neurodegenerative diseases, the current approach of targeting single pathways may be inadequate. Instead, broader therapeutic approaches that target the brain aging process directly may be considered as a new approach to treating neurodegenerative diseases. Further research into understanding nine hallmarks of aging and targeting these processes may be required to create effective new therapies for neurodegeneration. Some approaches being explored are described below:
====Supplementing NAD+ ====
[[NAD+]] is an essential molecule involved in energy metabolism in the body. A sufficient supply of NAD+ is necessary for maintenance of mitochondrial health, DNA repair, energy homeostasis and brain health. Levels of NAD+ decline with age in humans<ref>[https://pubmed.ncbi.nlm.nih.gov/27304511/ Camacho-Pereira J, Tarragó MG, Chini CCS, Nin V, Escande C, Warner GM, Puranik AS, Schoon RA, Reid JM, Galina A, Chini EN. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metab. 2016 Jun 14;23(6):1127-1139. doi: 10.1016/j.cmet.2016.05.006. PMID: 27304511; PMCID: PMC4911708.]</ref>, but supplementation can increase levels of NAD+. Supplementation with molecules that turn into NAD+, known as NAD+ precursors, include nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). These supplements may help to extend healthy lifespan and slow brain aging, thereby delaying or protecting against neurodegeneration. Supplementation of NAD+ in different models of Alzheimer's Disease has been shown to ameliorate amyloid-β and tau pathology, in addition to improvement in cognition<ref name=":5">[https://www.nature.com/articles/s41593-018-0332-9 Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, Lautrup S, Hasan-Olive MM, Caponio D, Dan X, Rocktäschel P, Croteau DL, Akbari M, Greig NH, Fladby T, Nilsen H, Cader MZ, Mattson MP, Tavernarakis N, Bohr VA. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci. 2019 Mar;22(3):401-412. doi: 10.1038/s41593-018-0332-9. Epub 2019 Feb 11. PMID: 30742114; PMCID: PMC6693625.]</ref>. Studies in mice have shown that NR can reduce plaque accumulation and improves cognition, as well as learning and memory '''''[Citation needed]'''''. NMN has similarly demonstrated beneficial effects in mice<ref name=":5" />. Clinical trials evaluating the potential benefits of NAD+ in humans are currently underway.

==== Induction of Autophagy ====
Autophagy is a fundamental highly conserved cellular process that degrades cellular components through the use of lysosomes<ref name=":6">[https://www.nature.com/articles/s43587-021-00098-4 Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK, Bjedov I, Palikaras K, Simonsen A, Johansen T, Tavernarakis N, Rubinsztein DC, Partridge L, Kroemer G, Labbadia J, Fang EF. Autophagy in healthy aging and disease. Nat Aging. 2021 Aug;1(8):634-650. doi: 10.1038/s43587-021-00098-4. Epub 2021 Aug 12. PMID: 34901876; PMCID: PMC8659158.]</ref>. This process has been highly connected to the process of aging and age-related diseases, and several compounds that can induce autophagy, such as rapamycin, spermidine, urolithin A, and others, have been shown to positively impact lifespan<ref name=":6" />. Dysfunctional acidification of the autolysosome is present in mouse models of Alzheimer's Disease<ref>Lee JH, Yang DS, Goulbourne CN, Im E, Stavrides P, Pensalfini A, Chan H, Bouchet-Marquis C, Bleiwas C, Berg MJ, Huo C, Peddy J, Pawlik M, Levy E, Rao M, Staufenbiel M, Nixon RA. Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci. 2022 Jun;25(6):688-701. doi: 10.1038/s41593-022-01084-8. Epub 2022 Jun 2. PMID: 35654956; PMCID: PMC9174056.</ref>. Stimulation of autophagy through rapamycin and trehalose for instance, can ameliorate tau pathology in mice<ref>Ozcelik S, Fraser G, Castets P, Schaeffer V, Skachokova Z, Breu K, Clavaguera F, Sinnreich M, Kappos L, Goedert M, Tolnay M, Winkler DT. Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. PLoS One. 2013 May 7;8(5):e62459. doi: 10.1371/journal.pone.0062459. PMID: 23667480; PMCID: PMC3646815.</ref><ref>Schaeffer V, Lavenir I, Ozcelik S, Tolnay M, Winkler DT, Goedert M. Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain. 2012 Jul;135(Pt 7):2169-77. doi: 10.1093/brain/aws143. Epub 2012 Jun 10. PMID: 22689910; PMCID: PMC3381726.</ref>.

Mitophagy, the selective autophagy degradation of mitochondria, has been shown to be reduced by 30-50% in the hippocampus of Alzheimer's patients<ref name=":5" /> and . The induction of mitophagy can ameliorate Aβ pathology and cognitive decline in AD mice, in addition to promote the phagocytic activity of microglia and reducing neuroinflammation<ref name=":5" />.

====Inhibition of cellular senescence====
Senescence of the astrocytes and microglial cells - cells that support neurons in the brain - accumulate in normal brain aging and patients with Parkinson's disease and Alzheimer's disease. The elimination of these cells may represent a new strategy for extending the healthspan of the brain and treating neurodegenerative diseases. Strategies using have shown beneficial effects in animal models:

*Rapamycin has been shown to decelerate cellular senescence as one of perhaps several neuroprotective effects
*Metformin has been shown to suppress cellular senescence via activation of microRNA-processing proteins that reduce plaque build-up in Alzheimer's disease and Parkinson's disease.

==Clinical trials targeting age-related mechanisms of neurodegenerative disorders==
{| class="wikitable"
|+
!Hallmark of aging targeted
!Drug(s)
!Mechanism of action
!Disease
!Actual or Estimated trial completion date
!ClinicalTrials.gov Link
|-
|Altered intercellular communication
|Niacin
|Reducing inflammation
|Parkinson's disease
|April 2020
|https://clinicaltrials.gov/ct2/show/NCT03462680
|-
|Deregulated nutrient sensing
| Resveratrol
|Reducing insulin resistance
|Mild cognitive impairment
|June 2022
|https://clinicaltrials.gov/ct2/show/NCT02502253
|-
|Mitochondrial dysfunction
|Nicotinamide (vitamin B3)
|Improving mitochondrial function
|Alzheimer's disease or MCI
|July 2022
|https://clinicaltrials.gov/ct2/show/NCT03061474
|-
|Mitochondrial dysfunction
|Nicotinamide (vitamin B3)
|Improving mitochondrial function
|Parkinson's disease
|March 2024
|https://clinicaltrials.gov/ct2/show/NCT03568968
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Alzheimer's disease
|August 2023
|https://clinicaltrials.gov/ct2/show/NCT04063124
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Mild cognitive impairment
|July 2031
|https://clinicaltrials.gov/ct2/show/NCT04685590
|-
|Cellular Senescence
|Dasatinib plus Quercetin
|Removing senescent cells
|Mild cognitive impairment
|June 2023
|https://clinicaltrials.gov/ct2/show/NCT04785300
|-
|Cellular Senescence
|Dasatinib plus Quercetin, Fisetin
|Removing senescent cells
|Skeletal health
|March 2023
|https://clinicaltrials.gov/ct2/show/NCT04313634
|-
|Multiple hallmarks
|Rapamycin
|Inhibiting mTOR pathway
|Mild cognitive impairment or early Alzheimer's disease
|December 2022
|https://clinicaltrials.gov/ct2/show/NCT04200911
|-
|Multiple hallmarks
|Rapamycin
|Inhibiting mTOR pathway
|Mild cognitive impairment or early Alzheimer's disease
|August 2024
|https://clinicaltrials.gov/ct2/show/NCT04629495
|}

==References==
<references />
[[Category:Longevity]]