Fight Aging!

Models are not reflections of real systems, but are better thought of as tools to help us understand how real systems might work under the hood. The production, assessment, and consideration of models over time helps researchers to constrain and guide research into real systems. Any individual model may not be all that helpful on its own. Certainly, its conclusions have to be considered in the context of the assumptions it makes and the behavior of different models in the same field.

Today's open access model discusses the Saturating-Removal model of aging, derived from observations of the growth in senescent cell burden with age and its contribution to degenerative aging. It is a form of damage accumulation model, perhaps more akin to reliability theory as applied to aging than other modeling in the field, though still quite different from that approach. The paper is an interesting read. As one might expect, the model of damage accumulation predicts that methods of damage repair - i.e. rejuvenation therapies that address issues such as senescent cell accumulation - will be needed to move the needle on human life span.

Maximal human lifespan in light of a mechanistic model of aging

There is a gap in understanding the rigidity of maximal human lifespan in terms of molecular and cellular mechanisms of aging. Despite advances in characterizing the molecular and cellular changes with age in humans and model organisms, it is unclear which mechanisms affect median and maximal lifespan differentially. For example, although it is often thought that aging is due to accumulating damage, it is not known how median and maximal lifespan are differentially affected by damage production rate, removal rate, stochastic noise, and threshold for death. Understanding which factors affect maximal lifespan may offer clues for future longevity interventions.

To address this, we applied an advance that links mechanistic aging processes to demographic variables such as median and maximal lifespan. This advance is a mathematical model of stochastic damage accumulation called the Saturating-Removal (SR) model (see chapter seven in Systems Medicine as a point of reference). The SR model was developed based on dynamics of senescent cells in mice and has since been shown to capture a wide range of aging patterns including the exponential rise in hazard with slowdown at old age, exponential disease incidence, effect of parabiosis, longevity interventions and their combinations, and aging differences between species. Recently, the model has been used to reexamine the heritability of human lifespan and provide insights into the compression of morbidity.

Here we show that variation in human lifespan is consistent with person-to-person differences in SR model parameters, subject to a strong constraint. Differences in damage production or removal rates greater than a few percent produce unrealistically long lifespans, whereas variation in threshold or noise preserves the observed upper limit near 120 years. This pattern is supported by analyses of NHANES exposure cohorts, centenarian sibling data, ages of the longest-lived individuals, and historical cohorts adjusted for extrinsic mortality. As a contrasting case, survival curves from Hutchinson-Gilford progeria - a disorder of accelerated aging due to nuclear lamina defects - indicate altered production dynamics.

Finally, we extended our analysis to additional mathematical models of aging and mortality and show that similar constraints apply. Together, these findings suggest that damage production and removal parameters in humans are tightly constrained with little person-to-person differences. Extending maximal human lifespan will require modifying the production or removal of aging-related damage, processes that appear largely unaffected by lifestyle, historical improvements, or common genetic variation.