Do Methods Known to Slow Aging Actually Slow Aging?

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.

Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J Mice

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.


Interesting, but fundamentally seems like navel-gazing to me - though possible conceptual and practical therapies may result. Better, perhaps, to make a list of preferred goals, including those only marginally desirable and those which may not occur even this century, if ever, say:
a) live forever in the body/mind of my 25-year-old self
b) live forever in the body/mind of my 65-year-old (future) self
c) live forever in the body/mind of my 85-year-old (future) self (assume reading, driving, independent, total life memory, full meals)
d) function forever with my 65-year-old cognition and memories in a reasonable organic sensory container that can interact with the world
e) function forever with my 65-year-old cognition and memories in an artificial container, minimal interaction
f) function forever with my 85-year-old cognition and memories in a reasonable organic sensory container that can interact with the world
g) function forever with my 85-year-old cognition and memories in an artificial container, minimal interaction
h) live until 150 with my 85-year-old-equivalent cognition and memories past 120 until the last 5 years
i) cryo-preserved with my 65-year-old cognition and memories, full function, wake up 200 years+ into future - ageing cured
j) cryo-preserved with my 85-year-old cognition and memories, full function, wake up 200 years+ into future - ageing cured
Some may lie on different paths from others. How many paths? The point is that many of these may be at different milestones along the same path, which may minimize over-distribution and over-extension of resources. This may further prioritize one's likely choices depending on what stage of life/ resources one has. Realizing that some artificial substitution may be required to maintain your 'essence' (whatever that is) may have to be considered. Business supply and demand need adjust accordingly.

Posted by: Jer at April 22nd, 2022 4:09 PM

It would be good if the lifepsan machine 2.0 project was further along and labs could cheaply test known interventions against Daphina (water fleas).

In the initial validation of the setup they showed that Metformin did not increase Daphina lifespan. Getting results for D+Q, rapamycin etc would also be a good sanity test.

Of course Daphina might have as many problems as mice when it comes to acting as a model for human lifepsan increases, but using both models together should hopefully reduce noise as each models defects are hopefully unrelated.

Posted by: jimofoz at April 23rd, 2022 5:21 AM
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