Negligible senescence

From Longevity Wiki

Definition

Negligible senescence refers to an absence of gradual deterioration with age, specifically an absence of:

  1. age-related increases in disease incidence and associated death rate;
  2. decrease in reproductive capability; and
  3. deterioration in physiological capacity, such as strength, mobility and sensory acuity.

It should be noted that negligible senescence is not synonymous with immortality. An organism that displays negligible senescence - i.e. no gradual deterioration - can still die of a sudden process, whether internal or external, such as predator attack, accident, starvation, exposure to adverse environmental conditions, disease or semelparity.

Examples of animals considered negligibly senescent

Naked mole rat (Heterocephalus glaber)

The naked mole rat is the only mammal known to meet all three criteria of negligible senescence, thought it must be noted that some controversy still exists:[1][2][3]

1. No age-related increases in disease incidence and associated death rate:

In the first two months of life babies are at increased risk of death from inadequate maternal care, cannibalism by siblings and poor inoculation of gastrointestinal flora and fauna. However, after this initial period the rate of death by natural causes is distributed randomly among all age groups rather than showing any age-related increase, except towards the end of the maximum species life span (i.e. the longest a member of the species has been observed to live), when there is believed to be a sudden increase in death rate.

2. No decrease in reproductive capability:

Breeding females show no menopause or decline in fertility, even after age 30. In fact, litter size tends to increase with age, although the pups born to older breeders are at greater risk of dying before weaning, possibly because of inadequate milk supply or because of greater disturbance to the larger colonies where these older breeders tend to be found.

The long lifespan of breeding females casts doubt on most evolutionary theories of aging, which generally propose that there is a trade-off between fecundity and lifespan, as energy invested in reproduction is not invested in repairing and maintaining the body.

3. No deterioration in physiological capacity, such as strength, mobility and sensory acuity:

Body composition is maintained from age 2 to age 24.

Naked mole rats have low susceptibility to disease. Notably, neoplasm has not yet been observed in this species.

Aldabra giant tortoise

Maximum observed life span: 255 years

Rougheye rockfish (Sebastes aleutianus)

Maximum observed lifespan: 205 years

Lobster

Scientists do not currently have a way of establishing the age of lobsters with certainty, but it has been estimated[4] that male European lobsters in the wild have an average life span of 31 years and a maximum of 42 ± 5, while females have an average life span of 54 years and a maximum of 72 ± 9.

Lake sturgeon (Acipenser fulvescens)

Maximum observed life span: 152 years

Ocean quahog (Arctica islandica)

Bivalve molluscs [5]provide the widest range of lifespans available for interspecies comparisons. The maximal lifespan in different populations of bivalve molluscs ranges from 36 for the Atlantic surfclam (Spisula solidissima) to >500 years for the ocean quahog (Arctica islandica), despite the similar size and living conditions. (Age is counted by growth rings on the shell). 

Sea urchin

Sea urchins[6] are widely used as model organisms for scientific research, part of their value being their close phylogenetic relationship to humans.

Sea urchins grow throughout their lives and can regenerate damaged appendages. Neoplasm is rare in these animals.

Some species of sea urchins show negligible senescence, and among these species there is a wide variation in maximum life span, ranging from 4 years (Lytechinus variegatus) to 100 years (Strongylocentrotus franciscanus).

Comparison between sea urchin species that show negligible senescence and those that do not and between species with different maximum life spans provides a useful opportunity to investigate factors affecting both aging and life span.

Studies of negligibly senescent sea urchins, of various species and with a range of maximum life spans, have shown maintenance of:

  • telomeres;
  • antioxidant and proteasome enzyme activities;
  • cellular pathways involved in energy metabolism, protein homeostasis and tissue regeneration

They have also shown a lack of major age-related accumulation of oxidative cellular damage.

The findings suggest that negligible senescence relies on the maintenance of mechanisms that sustain tissue homeostasis and regenerative capacity.

Strategies for engineered negligible senescence (SENS)[7]

Achieving (‘engineering’) negligible senescence in humans would not necessarily require damage to be prevented; rather, it would entail repairing damage as it occurs, rapidly and effectively enough that the functioning of the whole organism is not compromised – just as a vintage car can be kept in good working order if wear and tear is regularly repaired.

Where in the aging process to intervene in order to engineer negligible senescence

Aging can be modelled as a three-stage process:

  1. Metabolism: Metabolic processes produce toxins, some of which are not completely removed by the body’s repair mechanisms.
  2. Damage: As the toxins accumulate, they cause damage.  
  3. Pathology: The damage caused by the toxins drives age-related pathologies


Negligible senescence could be engineered by interrupting one of these stages.  

Stage 1 (metabolism) and stage 3 (pathology) are difficult to intervene in because they are dynamic processes where an intervention can set off a cascade of results.  

Stage 2 (damage) is a simpler target for intervention. This is because although damage itself can also cause dynamic reactions, removing damage is unlikely to do so. Furthermore, acting on stage 2 does not require an in-depth understanding of stages 1 and 3.  

Intervening in stage 2 requires identifying types of damage for which intervention might be needed. As such damage is age-related, a useful way to identify it is to compare the damage found in young people with that found in older people. 

Such damage appears to fall into seven categories:

  1. Cell loss
  2. Cell death resistance
  3. Cell overproliferation
  4. Intracellular ‘junk’
  5. Extracellular junk
  6. Tissue stiffening
  7. Mitochondrial defects

Efforts to develop strategies for engineered negligible senescence therefore focus on methods for mitigating each of the above types of damage, using either existing biotechnology or plausible extensions of it.

Why engineer negligible senescence?

  1. Compassionate motives: age-related deterioration has a negative impact on quality of life.  
  2. Economic motives: resources have to be dedicated to supporting those suffering from age-related deterioration. The deterioration also compromises their ability to carry out productive work.

Implications of deploying anti-senescence technologies widely

Widespread deployment of anti-senescence technologies would cause populations to surge. [8]

Advantages

  • The labor force would be larger and, on average, healthier, which would boost economic growth.

Disadvantages

  • The cost of implementing the anti-senescence technologies could still outweigh the resulting economic growth in some countries.
  • In order to finance citizens’ longer lives, governments would have to restructure their financing.
  • It might be necessary to eliminate retirement.
  • There would be much greater pressure on the environment.  


  1. Buffenstein, R. (2008). Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. Journal of Comparative Physiology B, 178(4), 439-445.
  2. Ruby, J. G., Smith, M., & Buffenstein, R. (2018). Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age. elife, 7, e31157.
  3. Ruby, J. G., Smith, M., & Buffenstein, R. (2018). Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age. elife, 7, e31157.
  4. https://cdnsciencepub.com/doi/abs/10.1139/f99-116
  5. Stenvinkel, P., & Shiels, P. G. (2019). Long-lived animals with negligible senescence: clues for ageing research. Biochemical Society Transactions, 47(4), 1157-1164.
  6. Bodnar, A. G. (2015). Cellular and molecular mechanisms of negligible senescence: insight from the sea urchin. Invertebrate reproduction & development, 59(sup1), 23-27.
  7. Zealley, B., & De Grey, A. D. (2013). Strategies for engineered negligible senescence. Gerontology, 59(2), 183-189.
  8. https://www.sciencedirect.com/science/article/pii/S0040162515001985