Metabolic flexibility - Revision history

Dmitry Dzhagarov at 12:04, 13 February 2024

2024-02-13T12:04:29Z

← Older revision		Revision as of 12:04, 13 February 2024
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	The general public is becoming more aware of the importance of metabolic flexibility, and companies like [https://www.lumen.me/metabolic-flexibility Lumen Metabolism] and [https://www.levelshealth.com Levels] are currently offering personalized dietary recommendations based on the measurement of an individuals’s metabolic flexibility.		The general public is becoming more aware of the importance of metabolic flexibility, and companies like [https://www.lumen.me/metabolic-flexibility Lumen Metabolism] and [https://www.levelshealth.com Levels] are currently offering personalized dietary recommendations based on the measurement of an individuals’s metabolic flexibility.

			== Metabolic slowdown ==
			Metabolic slowdown is consistently observed with ageing. Starting around age 60, resting metabolic rates (RMRs) declines by approximately 1% annually.<ref>Pontzer, H., Yamada, Y., Sagayama, H., Ainslie, P. N., Andersen, L. F., Anderson, L. J., ... & IAEA DLW Database Consortium §. (2021). Daily energy expenditure through the human life course. Science, 373(6556), 808-812. PMID: 34385400 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370708/ PMC8370708] DOI: 10.1126/science.abe5017</ref><ref>Willis, E. A., Herrmann, S. D., Hastert, M., Kracht, C. L., Barreira, T. V., Schuna Jr, J. M., ... & Ainsworth, B. E. (2024). Older Adult Compendium of Physical Activities: Energy costs of human activities in adults aged 60 and older. Journal of Sport and Health Science, 13(1), 13-17. PMID: 38242593 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10818108/ PMC10818108] DOI: 10.1016/j.jshs.2023.10.007</ref> In humans basal metabolic rate
			declines with age independent of the decline in fat-free mass (FFM) and a physically active lifestyle can only partly protect against loss of FFM in aging adults.<ref>Westerterp, K. R., Yamada, Y., Sagayama, H., Ainslie, P. N., Andersen, L. F., Anderson, L. J., ... & Speakman, J. R. (2021). Physical activity and fat-free mass during growth and in later life. The American journal of clinical nutrition, 114(5), 1583-1589. PMID: 34477824 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8574623/ PMC8574623] DOI: 10.1093/ajcn/nqab260</ref><ref>Heymsfield, S. B., & Fearnbach, N. (2021). Can increasing physical activity prevent aging-related loss of skeletal muscle?. The American Journal of Clinical Nutrition, 114(5), 1579-1580. PMID: 34476475 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8574632/ PMC8574632] DOI: 10.1093/ajcn/nqab283</ref> It is also evident in mice,<ref>Houtkooper, R. H., Argmann, C., Houten, S. M., Cantó, C., Jeninga, E. H., Andreux, P. A., ... & Auwerx, J. (2011). The metabolic footprint of aging in mice. Scientific reports, 1(1), 134.</ref><ref>Rogers, N. H., Landa, A., Park, S., & Smith, R. G. (2012). Aging leads to a programmed loss of brown adipocytes in murine subcutaneous white adipose tissue. Aging cell, 11(6), 1074-1083. PMID: 23020201 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839316/ PMC3839316] DOI: 10.1111/acel.12010</ref> cats and dogs.<ref>Groves, E. (2019). Nutrition in senior cats and dogs: how does the diet need to change, when and why?. Companion Animal, 24(2), 91-101. </ref>

	=== AMPK and mTORC1 as central energy and nutrient sensors ===		=== AMPK and mTORC1 as central energy and nutrient sensors ===
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	[[File:Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling.jpg\|center\|thumb\|400x400px\|Dietary restriction and AMPK increase lifespan in peripheral tissues via mitochondrial network remodelling. This requires a downstream crosstalk between fatty acid oxidation and peroxisomes to promote longevity. <ref>Weir, H., Yao, P., Huynh, F., Escoubas, C., Goncalves, R., & Burkewitz, K. et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. ''Cell Metabolism'', ''26''(6), 884-896.e5. doi: 10.1016/j.cmet.2017.09.024</ref>]]		[[File:Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling.jpg\|center\|thumb\|400x400px\|Dietary restriction and AMPK increase lifespan in peripheral tissues via mitochondrial network remodelling. This requires a downstream crosstalk between fatty acid oxidation and peroxisomes to promote longevity. <ref>Weir, H., Yao, P., Huynh, F., Escoubas, C., Goncalves, R., & Burkewitz, K. et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. ''Cell Metabolism'', ''26''(6), 884-896.e5. doi: 10.1016/j.cmet.2017.09.024</ref>]]

			== References ==
	<references />		<references />
	{{DEFAULTSORT:Metabolic flexibility}}		{{DEFAULTSORT:Metabolic flexibility}}
	[[Category:Main list]]		[[Category:Main list]]
	[[Category:Aging pathways and hallmarks]]		[[Category:Aging pathways and hallmarks]]

Dmitry Dzhagarov: /* AMPK and mTORC1 as central energy and nutrient sensors */

2023-10-12T05:46:53Z

AMPK and mTORC1 as central energy and nutrient sensors

← Older revision		Revision as of 05:46, 12 October 2023
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	On the other hand, the mTOR pathway (and specifically mTORC1) acts as the anabolic counterpart and functions to sense fed states or high availability of nutrients. It is a known pro-aging pathway and is suppressed by metabolic states like [[fasting]] or [[Calorie restriction\|caloric restriction]]. Interventions such as [[rapamycin]] inhibit mTORC1 and are therefore believed to have a pro-longevity effect.		On the other hand, the mTOR pathway (and specifically mTORC1) acts as the anabolic counterpart and functions to sense fed states or high availability of nutrients. It is a known pro-aging pathway and is suppressed by metabolic states like [[fasting]] or [[Calorie restriction\|caloric restriction]]. Interventions such as [[rapamycin]] inhibit mTORC1 and are therefore believed to have a pro-longevity effect.
			Ubiquitous inhibition of mTORC1 extends lifespan in multiple organisms but also disrupts several anabolic processes resulting in stunted growth, slowed development, reduced fertility, and disrupted metabolism. It has been shown that targeting mTORC1 specifically in the nervous system in ''C. elegans'' (for example, using neuron-specific degradation of RAGA-1, an upstream activator of mTORC1) uncouples longevity from growth and reproductive impairments, and thus many canonical effects of low mTORC1 activity are not required to promote healthy aging.<ref>Smith HJ, Lanjuin A, Sharma A, Prabhakar A, Nowak E, Stine PG, et al. (2023) Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans. PLoS Genet 19(9): e1010938. https://doi.org/10.1371/journal.pgen.1010938</ref>

	=== Mediators of metabolic flexibility ===		=== Mediators of metabolic flexibility ===

Andrea at 01:14, 16 August 2023

2023-08-16T01:14:32Z

← Older revision		Revision as of 01:14, 16 August 2023
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	The lifespan extension observed during both AMPK activation and [[calorie restriction]] (CR) requires mitochondrial network remodelling in C. ''elegans.''<ref name=":0" /> Animals with adynamic, permanently fused mitochondria are unable to respond to [[Fasting\|intermittent fasting]] (IF) and no longer have the associated lifespan extension.<ref name=":0" /> This means IF requires functional mitochondrial dynamics for its associated lifepan increase.		The lifespan extension observed during both AMPK activation and [[calorie restriction]] (CR) requires mitochondrial network remodelling in C. ''elegans.''<ref name=":0" /> Animals with adynamic, permanently fused mitochondria are unable to respond to [[Fasting\|intermittent fasting]] (IF) and no longer have the associated lifespan extension.<ref name=":0" /> This means IF requires functional mitochondrial dynamics for its associated lifepan increase.

	Surprisingly, permanently fusing mitochondria during aging is sufficient to double maximum lifespan in worms.<ref name=":0" /> This is believed to be due to more stable mitochondrial networks, which can no longer become unstructured during aging. However, these worms are no longer able to respond to metabolic stresses and therefore do not have additional lifespan extension from AMPK activation or calorie restriction interventions.		Surprisingly, permanently fusing mitochondria during aging to prevent fission and fusion is sufficient to double maximum lifespan in worms.<ref name=":0" /> This is believed to be due to more stable mitochondrial networks, which can no longer become unstructured during aging. However, these worms are no longer able to respond to metabolic stresses and therefore do not have additional lifespan extension from AMPK activation or calorie restriction interventions.

	Downstream of mitochondrial network homeostasis, peroxisome function and fatty acid oxidation are required to promote longevity during conditions of CR and AMPK activation.<ref name=":0" />		Downstream of mitochondrial network homeostasis, peroxisome function and fatty acid oxidation are required to promote longevity during conditions of CR and AMPK activation.<ref name=":0" />

Andrea: category change

2022-12-27T12:51:37Z

category change

← Older revision		Revision as of 12:51, 27 December 2022
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	<references />		<references />
	{{DEFAULTSORT:Metabolic flexibility}}		{{DEFAULTSORT:Metabolic flexibility}}
	[[Category:~~Longevity~~]]		[[Category:Main list]]
			[[Category:Aging pathways and hallmarks]]

Andrea: Added to intro

2022-08-31T11:30:07Z

Added to intro

← Older revision		Revision as of 11:30, 31 August 2022
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	Healthy young individuals are able to transition easily between feeding states (fed versus [[fasting]]) and between different fuels (carbohydrates versus fats) as sources of energy. On the contrary, obesity and aging appear to share in common the inability to maintain metabolic flexibility.<ref>Smith, R., Soeters, M., Wüst, R., & Houtkooper, R. (2018). Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. Endocrine Reviews, 39(4), 489-517. doi: 10.1210/er.2017-00211</ref>		Healthy young individuals are able to transition easily between feeding states (fed versus [[fasting]]) and between different fuels (carbohydrates versus fats) as sources of energy. On the contrary, obesity and aging appear to share in common the inability to maintain metabolic flexibility.<ref>Smith, R., Soeters, M., Wüst, R., & Houtkooper, R. (2018). Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. Endocrine Reviews, 39(4), 489-517. doi: 10.1210/er.2017-00211</ref>

			The general public is becoming more aware of the importance of metabolic flexibility, and companies like [https://www.lumen.me/metabolic-flexibility Lumen Metabolism] and [https://www.levelshealth.com Levels] are currently offering personalized dietary recommendations based on the measurement of an individuals’s metabolic flexibility.

	=== AMPK and mTORC1 as central energy and nutrient sensors ===		=== AMPK and mTORC1 as central energy and nutrient sensors ===

Andrea: /* */

2022-08-19T11:43:26Z

← Older revision		Revision as of 11:43, 19 August 2022
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	~~{{Draft-article}}~~

	Metabolic flexibility is the ability of an organism to adapt efficiently and rapidly to different metabolic and energy states.		Metabolic flexibility is the ability of an organism to adapt efficiently and rapidly to different metabolic and energy states.

Andrea: /* Mitochondrial dynamics in aging */

2022-08-12T14:03:33Z

Mitochondrial dynamics in aging

← Older revision		Revision as of 14:03, 12 August 2022
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	The lifespan extension observed during both AMPK activation and [[calorie restriction]] (CR) requires mitochondrial network remodelling in C. ''elegans.''<ref name=":0" /> Animals with adynamic, permanently fused mitochondria are unable to respond to [[Fasting\|intermittent fasting]] (IF) and no longer have the associated lifespan extension.<ref name=":0" /> This means IF requires functional mitochondrial dynamics for its associated lifepan increase.		The lifespan extension observed during both AMPK activation and [[calorie restriction]] (CR) requires mitochondrial network remodelling in C. ''elegans.''<ref name=":0" /> Animals with adynamic, permanently fused mitochondria are unable to respond to [[Fasting\|intermittent fasting]] (IF) and no longer have the associated lifespan extension.<ref name=":0" /> This means IF requires functional mitochondrial dynamics for its associated lifepan increase.

	Surprisingly, permanently fusing mitochondria during aging is sufficient to double maximum lifespan in worms.<ref name=":0" /> This is believed to be due to more stable mitochondrial networks, which can no longer become unstructured during aging. However, these worms are no longer able to respond to metabolic stresses and therefore do not have additional lifespan extension from calorie restriction interventions.		Surprisingly, permanently fusing mitochondria during aging is sufficient to double maximum lifespan in worms.<ref name=":0" /> This is believed to be due to more stable mitochondrial networks, which can no longer become unstructured during aging. However, these worms are no longer able to respond to metabolic stresses and therefore do not have additional lifespan extension from AMPK activation or calorie restriction interventions.

	Downstream of mitochondrial network homeostasis, peroxisome function and fatty acid oxidation are required to promote longevity during conditions of CR and AMPK activation.<ref name=":0" />		Downstream of mitochondrial network homeostasis, peroxisome function and fatty acid oxidation are required to promote longevity during conditions of CR and AMPK activation.<ref name=":0" />

Andrea: /* AMPK and mTORC1 as central energy and nutrient sensors */

2022-08-12T13:44:41Z

AMPK and mTORC1 as central energy and nutrient sensors

← Older revision		Revision as of 13:44, 12 August 2022
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	{{Draft-article}}		{{Draft-article}}

	~~Put simply, metabolic~~ flexibility is the ability of an organism to adapt efficiently and rapidly to different metabolic and energy states. Healthy young individuals are able to transition easily between feeding states (fed versus [[fasting]]) and between different fuels (carbohydrates versus fats) as sources of energy. On the contrary, obesity and aging appear to share in common the inability to maintain metabolic flexibility.<ref>Smith, R., Soeters, M., Wüst, R., & Houtkooper, R. (2018). Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. Endocrine Reviews, 39(4), 489-517. doi: 10.1210/er.2017-00211</ref>		Metabolic flexibility is the ability of an organism to adapt efficiently and rapidly to different metabolic and energy states.

			Healthy young individuals are able to transition easily between feeding states (fed versus [[fasting]]) and between different fuels (carbohydrates versus fats) as sources of energy. On the contrary, obesity and aging appear to share in common the inability to maintain metabolic flexibility.<ref>Smith, R., Soeters, M., Wüst, R., & Houtkooper, R. (2018). Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. Endocrine Reviews, 39(4), 489-517. doi: 10.1210/er.2017-00211</ref>

	=== AMPK and mTORC1 as central energy and nutrient sensors ===		=== AMPK and mTORC1 as central energy and nutrient sensors ===
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	Downstream of mitochondrial network homeostasis, peroxisome function and fatty acid oxidation are required to promote longevity during conditions of CR and AMPK activation.<ref name=":0" />		Downstream of mitochondrial network homeostasis, peroxisome function and fatty acid oxidation are required to promote longevity during conditions of CR and AMPK activation.<ref name=":0" />
	[[File:Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling.jpg\|center\|thumb\|400x400px\|~~Graphical abstract from Weir et al.~~ Dietary restriction and AMPK increase lifespan in peripheral tissues via mitochondrial network and ~~peroxisome remodelling~~. <ref>Weir, H., Yao, P., Huynh, F., Escoubas, C., Goncalves, R., & Burkewitz, K. et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. ''Cell Metabolism'', ''26''(6), 884-896.e5. doi: 10.1016/j.cmet.2017.09.024</ref>]]		[[File:Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling.jpg\|center\|thumb\|400x400px\|Dietary restriction and AMPK increase lifespan in peripheral tissues via mitochondrial network remodelling. This requires a downstream crosstalk between fatty acid oxidation and peroxisomes to promote longevity. <ref>Weir, H., Yao, P., Huynh, F., Escoubas, C., Goncalves, R., & Burkewitz, K. et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. ''Cell Metabolism'', ''26''(6), 884-896.e5. doi: 10.1016/j.cmet.2017.09.024</ref>]]

	<references />		<references />
	{{DEFAULTSORT:Metabolic flexibility}}		{{DEFAULTSORT:Metabolic flexibility}}
	[[Category:Longevity]]		[[Category:Longevity]]

Andrea: /* Mitochondrial dynamics in aging */

2022-08-12T13:40:10Z

Mitochondrial dynamics in aging

← Older revision		Revision as of 13:40, 12 August 2022
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	==== Mitochondrial dynamics in aging ====		==== Mitochondrial dynamics in aging ====
	During aging, wild-type worms fed ''ad libitum'' display an increasingly disorganised and unstructured network of mitochondria. ~~And on the right they showed that intermitting~~ fasting ~~does in fact remodel~~ the mitochondrial network with a more structured state during fasting states and a more disorganised morphology during fed states~~, and they showed this is the case at different age of the animals~~.		During aging, wild-type worms fed ''ad libitum'' display an increasingly disorganised and unstructured network of mitochondria. [[Fasting\|Intermitting fasting]] remodels the mitochondrial network with a more structured state during fasting states and a more disorganised morphology during fed states.<ref name=":0" />

			The lifespan extension observed during both AMPK activation and [[calorie restriction]] (CR) requires mitochondrial network remodelling in C. ''elegans.''<ref name=":0" /> Animals with adynamic, permanently fused mitochondria are unable to respond to [[Fasting\|intermittent fasting]] (IF) and no longer have the associated lifespan extension.<ref name=":0" /> This means IF requires functional mitochondrial dynamics for its associated lifepan increase.

			Surprisingly, permanently fusing mitochondria during aging is sufficient to double maximum lifespan in worms.<ref name=":0" /> This is believed to be due to more stable mitochondrial networks, which can no longer become unstructured during aging. However, these worms are no longer able to respond to metabolic stresses and therefore do not have additional lifespan extension from calorie restriction interventions.

	The lifespan extension observed during both AMPK activation and [[calorie restriction]] requires mitochondrial network remodelling in C. ''elegans.''<ref name=":0" /> Animals with adynamic mitochondria (which have impaired mitochondrial dynamics) are unable to respond to intermittent fasting and have no associated lifespan extension.<ref name=":0" />		Downstream of mitochondrial network homeostasis, peroxisome function and fatty acid oxidation are required to promote longevity during conditions of CR and AMPK activation.<ref name=":0" />
			[[File:Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling.jpg\|center\|thumb\|400x400px\|Graphical abstract from Weir et al. Dietary restriction and AMPK increase lifespan in peripheral tissues via mitochondrial network and peroxisome remodelling. <ref>Weir, H., Yao, P., Huynh, F., Escoubas, C., Goncalves, R., & Burkewitz, K. et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. ''Cell Metabolism'', ''26''(6), 884-896.e5. doi: 10.1016/j.cmet.2017.09.024</ref>]]
	~~Strikingly, this was not the case with [[Calorie restriction\|dietary restriction]], in which adynamic mitochondria had no effect in the lifespan phenotype of worms. Therefore, the requirement~~ of ~~different~~ mitochondrial network ~~states appears to be context-specific~~, ~~highlighting the complexity of molecular pathways regulating longevity. Lastly, the Mair lab showed that mitochondrial network homeostasis promotes longevity by downstream coordination of~~ peroxisome function and fatty acid oxidation.<ref name=":0" />
	[[File:Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling.jpg\|center\|thumb\|400x400px\|~~'''Figure 2.'''~~ Graphical abstract from Weir et al. Dietary restriction and AMPK increase lifespan in peripheral tissues via mitochondrial network and peroxisome remodelling. <ref>Weir, H., Yao, P., Huynh, F., Escoubas, C., Goncalves, R., & Burkewitz, K. et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. ''Cell Metabolism'', ''26''(6), 884-896.e5. doi: 10.1016/j.cmet.2017.09.024</ref>]]

	<references />		<references />
	{{DEFAULTSORT:Metabolic flexibility}}		{{DEFAULTSORT:Metabolic flexibility}}
	[[Category:Longevity]]		[[Category:Longevity]]

Andrea: /* in progress */

2022-08-12T13:03:44Z

in progress

← Older revision		Revision as of 13:03, 12 August 2022
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	{{Draft-article}}		{{Draft-article}}

	Put simply, metabolic flexibility is the ability of an organism to adapt efficiently and rapidly to different metabolic and energy states. ~~For instance, healthy~~ young individuals are able to transition easily between feeding states (fed versus fasting) or between different fuels (carbohydrates versus fats) as sources of energy. On the contrary, obesity and aging appear to share in common the inability to maintain metabolic flexibility<ref>Smith, R., Soeters, M., Wüst, R., & Houtkooper, R. (2018). Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. Endocrine Reviews, 39(4), 489-517. doi: 10.1210/er.2017-00211</ref>.		Put simply, metabolic flexibility is the ability of an organism to adapt efficiently and rapidly to different metabolic and energy states. Healthy young individuals are able to transition easily between feeding states (fed versus [[fasting]]) and between different fuels (carbohydrates versus fats) as sources of energy. On the contrary, obesity and aging appear to share in common the inability to maintain metabolic flexibility.<ref>Smith, R., Soeters, M., Wüst, R., & Houtkooper, R. (2018). Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. Endocrine Reviews, 39(4), 489-517. doi: 10.1210/er.2017-00211</ref>

	=== AMPK and mTORC1 as central energy and nutrient sensors ===		=== AMPK and mTORC1 as central energy and nutrient sensors ===
	There are a variety of sensors controlling metabolic flexibility in an organism. The ~~two main~~ systems ~~regulating~~ metabolic flexibility are ~~considered to be~~ AMPK and mTORC1, both highly conserved across ~~different organisms,~~ including nematodes, flies, mice and humans ~~('''Figure 1''')~~.		[[File:Diagram of AMPK and MTORC1.png\|thumb\|AMPK and mTORC1 are the main energy and nutrient sensors regulating metabolic plasticity. They work coordinately to achieve an optimal energy balance and organismal homeostasis.<ref>Xu, J., Ji, J., & Yan, X. (2012). Cross-Talk between AMPK and mTOR in Regulating Energy Balance. ''Critical Reviews In Food Science And Nutrition'', ''52''(5), 373-381. doi: 10.1080/10408398.2010.500245</ref> Diagram extracted from the Lectures Series “''Is Aging Inevitable? - Webinar with William B. Mair''".<ref>https:://vimeo.com/523565896</ref>]]
			There are a variety of sensors controlling metabolic flexibility in an organism. The best known systems for metabolic flexibility are AMPK and mTORC1, both highly conserved across species including nematodes, flies, mice and humans.

	AMPK (AMP-activated protein kinase), is activated under catabolic conditions when intracellular ATP production is decreased. AMPK has key roles in regulating cellular growth, metabolism and [[autophagy]]. It is known as a pro-longevity pathway and is activated by states such as fasting or exercise.		AMPK (AMP-activated protein kinase), is activated under catabolic conditions when intracellular ATP production is decreased. AMPK has key roles in regulating cellular growth, metabolism and [[autophagy]]. It is known as a pro-longevity pathway and is activated by physiological states such as fasting or exercise.

	On the other hand, the mTOR pathway (and specifically mTORC1) acts as the anabolic counterpart and functions to sense fed states or high availability of nutrients. It is a known pro-aging pathway and is suppressed by states ~~such as~~ [[Calorie restriction\|caloric restriction]]. Interventions ~~like~~ [[rapamycin]] inhibit mTORC1 and are therefore believed to have a pro-longevity effect.		On the other hand, the mTOR pathway (and specifically mTORC1) acts as the anabolic counterpart and functions to sense fed states or high availability of nutrients. It is a known pro-aging pathway and is suppressed by metabolic states like [[fasting]] or [[Calorie restriction\|caloric restriction]]. Interventions such as [[rapamycin]] inhibit mTORC1 and are therefore believed to have a pro-longevity effect.

	~~[[File:Diagram~~ of ~~AMPK and MTORC1~~.~~png\|'''Figure 1.'''~~ AMPK ~~and mTORC1 are~~ the main ~~energy and nutrient sensors regulating metabolic plasticity. They work coordinately to achieve an optimal energy balance and organismal homeostasis~~.<ref>Xu, J., Ji, J., ~~& Yan~~, X. ~~(2012). Cross-Talk between AMPK and mTOR in Regulating Energy Balance. ''Critical Reviews In Food Science And Nutrition'', ''52''(5)~~, 373-381. doi: 10.1080/10408398.2010.500245</ref> Diagram extracted from the Lectures Series “''Is Aging Inevitable? - Webinar with William B. Mair''".<ref>https:://vimeo.com/523565896 </ref>\|center\|frameless\|650x650px]]'''Figure 1.''' AMPK and mTORC1 are the main energy and nutrient sensors regulating metabolic plasticity. They work coordinately to achieve an optimal energy balance and organismal homeostasis.<ref>Xu, J., Ji, J., & ~~Yan~~, X. (~~2012~~). ~~Cross-Talk between~~ AMPK and ~~mTOR in Regulating Energy Balance~~. ~~''Critical Reviews In Food Science And Nutrition''~~, ~~''52''~~(5), ~~373~~-~~381~~. doi: 10.~~1080~~/~~10408398~~.~~2010~~.~~500245~~</ref> ~~Diagram extracted from the Lectures Series “''Is Aging Inevitable?~~ - ~~Webinar with William B. Mair''".<ref>https:://vimeo~~.~~com/523565896</ref>~~		=== Mediators of metabolic flexibility ===
			The research group led by William Mair’s lab at Harvard University, proposes that loss of this metabolic flexibility during aging (ie. the proper activation/suppression of mTOR/AMPK pathways) is the main risk factor for the onset of age-related diseases.<ref name=":0">Weir, H., Yao, P., Huynh, F., Escoubas, C., Goncalves, R., & Burkewitz, K. et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. Cell Metabolism, 26(6), 884-896.e5. doi: 10.1016/j.cmet.2017.09.024</ref> Following this hypothesis, Mair’s lab is focused on defining molecular mediators of distinct metabolic states to develop novel therapeutic strategies against age-related diseases.

	~~=== Mediators of metabolic flexibility ===~~		An example of such mediators in C. ''elegans'' are CRTCs (CREB-regulated transcriptional coactivators) and the transcription factor CREB (cAMP-response element binding protein).<ref name=":1">Mair, W., Morantte, I., Rodrigues, A., Manning, G., Montminy, M., Shaw, R., & Dillin, A. (2011). Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature, 470(7334), 404-408. doi: 10.1038/nature09706</ref> CRTCs are a family of cofactors involved in a variety of physiological processes such as energy homeostasis in insulin-sensitive tissues.<ref>Altarejos, J., & Montminy, M. (2011). CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nature Reviews Molecular Cell Biology, 12(3), 141-151. doi: 10.1038/nrm3072</ref> They are conserved in humans and have been linked to age-related diseases such as type-2 diabetes.<ref>Berdeaux, R., & Hutchins, C. (2019). Anabolic and Pro-metabolic Functions of CREB-CRTC in Skeletal Muscle: Advantages and Obstacles for Type 2 Diabetes and Cancer Cachexia. Frontiers In Endocrinology, 10. doi: 10.3389/fendo.2019.00535</ref>
	The research group led by William Mair’s lab at Harvard University, have hypothesised that the loss of this metabolic flexibility with age (or the proper activation/suppression of mTOR/AMPK pathway) is the main risk factor for the onset of age-related diseases<ref name=":0">Weir, H., Yao, P., Huynh, F., Escoubas, C., Goncalves, R., & Burkewitz, K. et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. Cell Metabolism, 26(6), 884-896.e5. doi: 10.1016/j.cmet.2017.09.024</ref>. Following this hypothesis, Mair’s lab is focused on defining molecular mediators of different metabolic states to develop novel therapeutic strategies against age-related diseases. An example of such mediators in C. ''elegans'' are CRTCs (CREB-regulated transcriptional coactivators) and the transcription factor CREB (cAMP-response element binding protein)<ref name=":1">Mair, W., Morantte, I., Rodrigues, A., Manning, G., Montminy, M., Shaw, R., & Dillin, A. (2011). Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature, 470(7334), 404-408. doi: 10.1038/nature09706</ref>, a family of cofactors involved in a variety of physiological processes~~, including~~ energy homeostasis in insulin-sensitive tissues<ref>Altarejos, J., & Montminy, M. (2011). CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nature Reviews Molecular Cell Biology, 12(3), 141-151. doi: 10.1038/nrm3072</ref>. CRTCs and CREB were shown to mediate the lifespan extension of calcineurin and of constitutive activation of the AMPK pathway<ref name=":1" />. By disrupting a component of the AMPK complex acting as the key energy sensor, they managed to genetically mimic dietary restriction and extend lifespan in C. ''elegans'' by 50%, despite worms being fed ''ad libitum''<ref name=":1" />. Interestingly, CRTCs are conserved in humans and have been linked to age-related diseases such as type-2 diabetes<ref>Berdeaux, R., & Hutchins, C. (2019). Anabolic and Pro-metabolic Functions of CREB-CRTC in Skeletal Muscle: Advantages and Obstacles for Type 2 Diabetes and Cancer Cachexia. Frontiers In Endocrinology, 10. doi: 10.3389/fendo.2019.00535</ref>.
			Constitutive activation of AMPK can be achieved by disrupting an energy sensor component of the AMPK complex and leads to a lifespan extension of 50% in C. ''elegans''.<ref name=":1" /> This intervention genetically mimics dietary restriction despite worms being fed ''ad libitum.'' Activation of AMPK and inhibition of calcineurin extend lifespan via CRTCs and CREB in the nervous tissue and requires remodelling of the mitochondria and peroxisome network.<ref name=":1" /> More recently, it has been shown that CRTC-1 in the neurons drives cell non-autonomous regulation of mitochondrial dynamics in other tissues and modulate lifespan.<ref>Zhang, Y., Lanjuin, A., Chowdhury, S., Mistry, M., Silva-García, C., & Weir, H. et al. (2019). Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans. ''Elife'', ''8''. doi: 10.7554/elife.49158</ref>

	=== Mitochondrial dynamics ===		=== Mitochondrial dynamics ===
	~~A key cellular process required for efficient metabolic flexibility is the remodelling of the mitochondrial network<ref name=":0" />.~~ [[Mitochondria]] are highly dynamic organelles found in most eukaryotes and commonly referred to as the powerhouses of the cell. ~~They~~ undergo coordinated cycles of fission and fusion in order to maintain their shape, distribution and size~~, as shown by imaging studies in live cell~~<ref>Okamoto, K., & Shaw, J. (2005). Mitochondrial Morphology and Dynamics in Yeast and Multicellular Eukaryotes. Annual Review Of Genetics, 39(1), 503-536. doi: 10.1146/annurev.genet.38.072902.093019</ref><ref>Tilokani, L., Nagashima, S., Paupe, V., & Prudent, J. (2018). Mitochondrial dynamics: overview of molecular mechanisms. Essays In Biochemistry, 62(3), 341-360. doi: 10.1042/ebc20170104</ref>. Besides metabolic flexibility, mitochondria dynamics also facilitate mitophagy (the [[autophagy]] of [[mitochondria]]~~), and~~ [[Mitochondrial Dysfunction\|~~mitochondrial~~ dysfunction]] is a hallmark of aging and has been implicated in age-related diseases such as [[Aging and Neurodegeneration\|Alzheimer’s and Parkinson’s diseas]]<nowiki/>e<ref>Bonda DJ, Smith MA, Perry G, Lee HG, Wang X, Zhu X. The mitochondrial dynamics of Alzheimer’s disease and Parkinson’s disease offer important opportunities for therapeutic intervention. Curr Pharm Des. 2011;17:3374–3380.</ref>.		[[Mitochondria]] are highly dynamic organelles found in most eukaryotes and commonly referred to as the powerhouses of the cell. Imaging studies in live cells show that mitochondria undergo coordinated cycles of fission and fusion in order to maintain their shape, distribution and size.<ref>Okamoto, K., & Shaw, J. (2005). Mitochondrial Morphology and Dynamics in Yeast and Multicellular Eukaryotes. Annual Review Of Genetics, 39(1), 503-536. doi: 10.1146/annurev.genet.38.072902.093019</ref><ref>Tilokani, L., Nagashima, S., Paupe, V., & Prudent, J. (2018). Mitochondrial dynamics: overview of molecular mechanisms. Essays In Biochemistry, 62(3), 341-360. doi: 10.1042/ebc20170104</ref>

			The activity of mitochondrial dynamics is highly context specific; its cycles of fission and fusion will depend on age of the animal, nutrient conditions (fasting versus feeding) and whether there is cellular damage. Besides metabolic flexibility, mitochondria dynamics also facilitate mitophagy, the [[autophagy]] of [[mitochondria]]. [[Mitochondrial Dysfunction\|Mitochondrial dysfunction]] is a hallmark of aging and has been implicated in age-related diseases such as [[Aging and Neurodegeneration\|Alzheimer’s and Parkinson’s diseas]]<nowiki/>e.<ref>Bonda DJ, Smith MA, Perry G, Lee HG, Wang X, Zhu X. The mitochondrial dynamics of Alzheimer’s disease and Parkinson’s disease offer important opportunities for therapeutic intervention. Curr Pharm Des. 2011;17:3374–3380.</ref>

			A key process required for efficient metabolic flexibility is the remodelling of the mitochondrial network.<ref name=":0" /> In other words, cells require mitochondrial dynamics to respond to certain changes in nutrient availability, cellular stresses and other molecular signals. For instance, during fasting mitochondria fuse together to enable more efficient respiration or metabolism, whilst during feeding states, mitochondria fragment, facilitating their mitophagy.

			==== Mitochondrial dynamics in aging ====
			During aging, wild-type worms fed ''ad libitum'' display an increasingly disorganised and unstructured network of mitochondria. And on the right they showed that intermitting fasting does in fact remodel the mitochondrial network with a more structured state during fasting states and a more disorganised morphology during fed states, and they showed this is the case at different age of the animals.



			The lifespan extension observed during both AMPK activation and [[calorie restriction]] requires mitochondrial network remodelling in C. ''elegans.''<ref name=":0" /> Animals with adynamic mitochondria (which have impaired mitochondrial dynamics) are unable to respond to intermittent fasting and have no associated lifespan extension.<ref name=":0" />

	Work from Weir et al showed that lifespan extension observed during AMPK activation and [[Calorie restriction\|dietary restriction]] requires mitochondrial network remodelling in C. ''elegans''<ref name=":0" />. In other words, cells require mitochondrial dynamics to respond to certain changes in nutrient availability, cellular stresses or other molecular signals. The Mair lab showed that adynamic mitochondria (with impaired mitochondrial dynamics) are unable to respond to intermittent fasting, preventing the associated lifespan extension<ref name=":0" />. Strikingly, this was not the case with [[Calorie restriction\|dietary restriction]], in which adynamic mitochondria had no effect in the lifespan phenotype of worms. Therefore, the requirement of different mitochondrial network states appears to be context-specific, highlighting the complexity of molecular pathways regulating longevity. Lastly, the Mair lab showed that mitochondrial network homeostasis promotes longevity by downstream coordination of peroxisome function and fatty acid oxidation ~~('''Figure 2''')~~<ref name=":0" />.		Strikingly, this was not the case with [[Calorie restriction\|dietary restriction]], in which adynamic mitochondria had no effect in the lifespan phenotype of worms. Therefore, the requirement of different mitochondrial network states appears to be context-specific, highlighting the complexity of molecular pathways regulating longevity. Lastly, the Mair lab showed that mitochondrial network homeostasis promotes longevity by downstream coordination of peroxisome function and fatty acid oxidation.<ref name=":0" />
	[[File:Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling.jpg\|center\|thumb\|400x400px\|'''Figure 2.''' Graphical abstract from Weir et al. Dietary restriction and AMPK increase lifespan in peripheral tissues via mitochondrial network and peroxisome remodelling. <ref>Weir, H., Yao, P., Huynh, F., Escoubas, C., Goncalves, R., & Burkewitz, K. et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. ''Cell Metabolism'', ''26''(6), 884-896.e5. doi: 10.1016/j.cmet.2017.09.024</ref>]]		[[File:Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling.jpg\|center\|thumb\|400x400px\|'''Figure 2.''' Graphical abstract from Weir et al. Dietary restriction and AMPK increase lifespan in peripheral tissues via mitochondrial network and peroxisome remodelling. <ref>Weir, H., Yao, P., Huynh, F., Escoubas, C., Goncalves, R., & Burkewitz, K. et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. ''Cell Metabolism'', ''26''(6), 884-896.e5. doi: 10.1016/j.cmet.2017.09.024</ref>]]