4 replies to this topic

[reason]

I recall being surprised by the study from a few years ago showing that early epigenetic clocks are insensitive to physical fitness, as demonstrated in twin studies using fit versus sedentary twin pairs. Given that a higher epigenetic age than chronological age, epigenetic age acceleration, correlates with increased mortality, and fitness status is similarly well correlated with mortality, it seems interesting that the machine learning approaches used to generate the clocks from raw epigenetic data by age managed to produce this outcome. Today's study is similarly surprising, and perhaps more so. It suggests that epigenetic age is not strongly correlated with inflammatory status, and yet it is well demonstrated that increased chronic inflammation in aging drives all of the common age-related conditions, raises mortality risk, and is in general an important component in degenerative aging.

The true promise of epigenetic clocks (and similarly, transcriptomic and other clocks) is to be able to test potential rejuvenation therapies, determining quickly and efficiently whether or not they work, and how good they are relative to other options. As things stand today the research and development communities spend far too much time and effort on marginal therapies. Some process by which poor approaches are cost-effectively winnowed out early on in the development process is very much needed. Ideally, an epigenetic clock measurement would be taken before and after an intervention is attempted, either in mice or in human trials, and provide an unambiguous result. Unfortunately, epigenetic clocks cannot be used in this fashion for so long as they have these gaps, unknown until discovered, in which important aspects of aging are not well reflected in epigenetic age.

Inflammation and epigenetic ageing are largely independent markers of biological ageing and mortality

Limited evidence exists on the link between inflammation and epigenetic ageing. We aimed to 1) assess the cross-sectional and prospective associations of 22 inflammation-related plasma markers and a signature of inflammaging with epigenetic ageing; 2) determine whether epigenetic ageing and inflammaging are independently associated with mortality. Blood samples from 940 participants in the Melbourne Collaborative Cohort Study, collected at baseline (1990-1994) and follow-up (2003-2007) were assayed for DNA methylation and 22 inflammation-related markers, including well-established markers (e.g., interleukins and C-reactive protein) and metabolites of the tryptophan-kynurenine pathway. Four measures of epigenetic ageing (PhenoAge, GrimAge, DunedinPoAm and Zhang) and a signature of inflammaging were considered.

Associations were assessed using linear regression, and mortality hazard ratios (HR) were estimated using Cox regression. Cross-sectionally, most inflammation-related markers were associated with epigenetic ageing measures, although with generally modest effect sizes and explaining altogether between 1% and 11% of their variation. Prospectively, baseline inflammation-related markers were not, or only weakly, associated with epigenetic ageing after 11 years of follow-up. Epigenetic ageing and inflammaging were strongly and independently associated with mortality, e.g. inflammaging: HR=1.41, which was only slightly attenuated after adjustment for four epigenetic ageing measures: HR=1.35. Although cross-sectionally associated with epigenetic ageing, inflammation-related markers accounted for a modest proportion of its variation. Inflammaging and epigenetic ageing are essentially non-overlapping markers of biological ageing and may be used jointly to predict mortality.

View the full article at FightAging

[Turnbuckle]

The researchers in the first linked paper state: "leisure time physical activity during adult years has at most a minor effect on DNAm age acceleration. This is consistent with recent findings that long-term leisure time physical activity in adulthood has little effect on mortality after controlling for genetic factors." Given that this is consistent, where is the problem? You state "fitness status is similarly well correlated with mortality," but correlations aren't proof of causation. The researchers state that, "It is possible that genetic pleiotropy affecting exercise participation might partly explain the frequently observed associations between physical activity and reduced mortality in humans." The implication is that cause and effect might be reversed from what was assumed. Those who exercise more do so because of superior genetics; they don't live longer because they exercise. Once you control for genetic factors, the correlation mostly goes away.

 

As for inflammation and epigenetic age both being correlated with mortality but only weakly correlated with each other, that makes perfect sense and is not surprising. If one deleted the word "epigenetic," I doubt that anyone would disagree that both age and inflammation contribute to mortality.

 

 

Edited by Turnbuckle, 14 August 2022 - 09:03 PM.

[Martini]

The researchers in the first linked paper state: "leisure time physical activity during adult years has at most a minor effect on DNAm age acceleration. This is consistent with recent findings that long-term leisure time physical activity in adulthood has little effect on mortality after controlling for genetic factors." Given that this is consistent, where is the problem? You state "fitness status is similarly well correlated with mortality," but correlations aren't proof of causation. The researchers state that, "It is possible that genetic pleiotropy affecting exercise participation might partly explain the frequently observed associations between physical activity and reduced mortality in humans." The implication is that cause and effect might be reversed from what was assumed. Those who exercise more do so because of superior genetics; they don't live longer because they exercise. Once you control for genetic factors, the correlation mostly goes away.

 

As for inflammation and epigenetic age both being correlated with mortality but only weakly correlated with each other, that makes perfect sense and is not surprising. If one deleted the word "epigenetic," I doubt that anyone would disagree that both age and inflammation contribute to mortality.

 

True, but inflammation undoubtedly causes aging, but only weak epigenetic aging according to the linked article. So epigenetic aging covers only a part of aging. At least that is the conclusion I draw from it.
 

[Turnbuckle]

True, but inflammation undoubtedly causes aging, but only weak epigenetic aging according to the linked article. So epigenetic aging covers only a part of aging. At least that is the conclusion I draw from it.
 

 

The way I read it, inflammation is a factor in mortality, not aging per se. 

[Martini]

The way I read it, inflammation is a factor in mortality, not aging per se. 

 

This would mean that age-related low-grade chronic inflammation and its markers are only indicators of aging, but not necessarily a factor per se. Thus, even measures that eliminate these inflammations would not lead to a slowing of aging, if the underlying aging processes were not changed.
Ultimately, one would then come to the conclusion that aging and thus also the success of measures that are supposed to prevent aging would have to be measured by the maximum achievable lifespan.