Fight Aging!

There are many different ways to conceptualize programs of research and development aimed at the treatment of aging. The Strategies for Engineered Negligible Senescence (SENS) is focused on aging as damage accumulation, and treatment is thus damage repair: remove senescent cells, restore mitochondrial function, clear out harmful protein aggregates, and so forth. Programmed aging viewpoints instead focus on ways to alter what are suspected to be evolved programs that drive aging, with this line of thought most often centered around the reversal of epigenetic changes that are observed to occur with age.

In today's open access paper, the authors propose a viewpoint that they call juventology, the study of youth, in analogy to gerontology, the study of aging. Clearly calorie restriction and related interventions adjust the operation of metabolism to slow aging and prolong the period of youthful life in many species. This might be taken as the existence of youth-maintaining programs, a delay of aging programs, or a slowing of damage accumulation. People tend to see their own view of aging reflected in the data for calorie restriction. It causes such a broad set of changes in cellular biochemistry, where that biochemistry is itself not fully mapped, that it is hard to mount arguments in support of one theory of aging versus another.

Is this really a good choice of strategy, however? Do we believe that calorie restriction is a starting point for a field that will in time engineer some form of altered metabolism that is far more effective when it comes to prolonging youthful life? In principle this has to be the case, as similar species with radically different life spans exist in the wild. Compare mice with naked mole-rats, for example, a nine-fold difference in life expectancy. In practice, I suspect that engineering human cellular metabolism to this degree is a far future prospect, however. The advantage of the damage repair approach is that it does seem to offer goals that can be achieved in the near future, without a full understanding of cellular biochemistry, and which will achieve meaningful gains in life span and reduction in the burden of age-related disease.

Exploring juventology: unlocking the secrets of youthspan and longevity programs

The paradigm of longevity programs opens up new vistas for understanding interventions that extend lifespan without instigating adverse effects. While traditional aging research has often fixated on combating free radicals and oxidative stress, juventology suggests that the most effective pro-longevity interventions induce alternate survival phases. The exploration of longevity programs in model organisms reveals a complex network of cellular responses and adaptive strategies that challenge the somewhat conventional theories of aging. Especially, the interplay between nutrient availability and the activation of specific longevity programs is not just a passive response but instead highlights a sophisticated network of cellular events that over the course of the lifespan can result in a healthier aging phenotype and increased longevity. In E. coli, Saccharomyces cerevisiae, and C. elegans, starvation, the most severe form of dietary restriction, causes a major lifespan extension.

Juventology is fundamentally different from "aging-centered" theories of aging for two reasons: (1) alternative lifespan programs, such as those entered in response to starvation, can be independent (or are at least partially independent) of aging itself. As an example, one could visualize the use of target-specific pharmaceuticals or systemically broader acting periodic fasting intervals modulate the mTor-S6K and PKA pathways, which in turn can promote regeneration and rejuvenation. Notably, this can be achieved even in an organism with a high rate of aging. Thus, even in an accelerated aging phenotype, a longer healthspan and lifespan may be accomplished by periodically activating regenerative and rejuvenating processes. (2) Juventology shifts the focus from an "old or older age" paradigm characterized by high degrees of dysfunction and subsequent high morbidity and mortality, instead to the period in life during which both morbidity and mortality are very low and only difficult to detect.

Diseases in humans are generally rare before the (biological) age 40, but comorbidities are common after age 65, yet no specific field of science is focusing on how evolution resulted in a program that is extremely efficient in preventing disease for the first 40 years of life and how that program may be modulated and extended by dietary, pharmacological, or other interventions. On the one hand, developmental biology focuses on the biological process from embryo to (young) adult stage and generally does not include this important field. On the other hand, biogerontology the biological basis of aging and age-related diseases. Thus, juventology presents a complementary field to both gerontology and developmental biology that focuses on the period of organismal life when the force of natural selection is high and body functions remain maximized.

Periodic fasting and calorie restriction promote cells to enter into a stress resistance state which is characterized by the activation of cell protection, regeneration, and rejuvenation processes. Across multiple species, these protective and regenerative mechanisms are activated in part by the down-regulation of growth hormone, IGF-1, mTor-S6K, and PKA signaling cascades, which in turn induces the extension of healthspan. Because these states have evolved to withstand periods of extreme nutrient starvation, they can be viewed as alternative longevity programs activated to maintain cellular "youthspan" until resources that promote proliferative processes become available again. Here, we propose that these juventology-based approaches provide complementary strategies to the classic biogerontology approaches to focus on the earlier (i.e., biologically younger) functional period while also studying the later progressively dysfunctional processes that affect health and longevity.