If you ever want to see an earnest debate, then put a bunch of modern biogerontologists into a room and ask them to (a) define what it means to slow aging, and (b) whether or not methods known to reduce mortality and extend life in animal studies actually slow aging. You might recall the discussion a decade or so ago over whether or not mTOR inhibition, which upregulates autophagy and reliably extends life in mice, actually slows aging or just suppresses cancer incidence. Mice being little cancer factories, a reduction in cancer incidence is sufficient to move the needle on life span. A sideline to that discussion is whether or not we should consider metabolic changes that do nothing but suppress cancer incidence to count as a form of slowing aging. Data gives way to definitional wars and the drawing of lines quite quickly.
Today's open access preprint paper provides a start on generalizing this sort of discussion about the nature of aging, slowing aging, and interventions that may or may not slow aging. The authors go beyond mTOR inhibition to add other interventions that also upregulate cellular stress responses. They conclude that it is possible that age-related decline in mice is postponed rather than slowed by lifelong use of this class of intervention. The rest of us can then debate whether or not that still counts as slowing aging. As a counterpoint to this preprint, it is clearly the case that mTOR inhibition does extend remaining life span in mice when started late in life. We are left wanting more data and a greater understanding of what is going on under the hood, as usual.
A large body of work, carried out over the past decades in a range of model organisms including yeast, worms, flies and mice, has identified hundreds of genetic variants as well as numerous dietary factors, pharmacological treatments, and other environmental variables that can increase the length of life in animals. Current concepts regarding the biology of aging are in large part based on results from these lifespan studies. Much fewer data, however, are available to address the question of whether these factors, besides extending lifespan, in fact also slow aging, particularly in the context of mammalian models.
It is important to distinguish lifespan vs. aging because it is well known that lifespan can be restricted by specific sets of pathologies associated with old age, rather than being directly limited by a general decline in physiological systems. In various rodent species, for instance, the natural end of life is frequently due to the development of lethal neoplastic disorders: cancers have been shown to account for ca. 70-90% of natural age-related deaths in a range of mouse strains. Accordingly, there is a strong need to study aging more directly, rather than to rely on lifespan as the sole proxy measure for aging.
'Aging' is used as a term to lump together the processes that transform young adult individuals (i.e., individuals that have attained full growth and maturity) into aged ones with functional changes across multiple physiological systems, elevated risk for multiple age-related diseases, and high mortality rates. It is associated with the accumulation of a large number of phenotypic changes, spanning across various levels of biological complexity (molecular, cellular, tissue and organismal level) and affecting virtually all tissues and organ systems. Aging can hence be approached analytically by assessing age-dependent phenotypic change, from young adulthood into old age, across a large number of age-sensitive traits covering multiple tissues, organ systems and levels of biological complexity.
Here, we employed large-scale phenotyping to analyze hundreds of phenotypes and thousands of molecular markers across tissues and organ systems in a single study of aging male C57BL/6J mice. For each phenotype, we established lifetime profiles to determine when age-dependent phenotypic change is first detectable relative to the young adult baseline. We examined central genetic and environmental lifespan regulators (putative anti-aging interventions, PAAIs; the following PAAIs were examined: mTOR loss-of-function, loss-of-function in growth hormone signaling, dietary restriction) for a possible countering of the signs and symptoms of aging. Importantly, in our study design, we included young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. In parallel to our studies in mice, we assessed genetic variants for their effects on age-sensitive phenotypes in humans.
We observed that, surprisingly, many PAAI effects influenced phenotypes long before the onset of detectable age-dependent changes, rather than altering the rate at which these phenotypes developed with age. Accordingly, this subset of PAAI effects does not reflect a targeting of age-dependent phenotypic change. Overall, our findings suggest that comprehensive phenotyping, including the controls built in our study, is critical for the investigation of PAAIs as it facilitates the proper interpretation of the mechanistic mode by which PAAIs influence biological aging.