Current Aging Clocks are Arguably Too Sensitive to Transient Stresses
Numerous clocks to assess biological age have been constructed based on comparisons of epigenetic, transcriptomic, proteomic, and other data that changes with age. When measured using white blood cells from a blood sample, one might argue that these clocks are overly influenced by the state of the immune system, changing in response to circumstances. With that in mind, researchers here report on the tendency of measured biological age to transiently increase during stressful circumstances. Aging clocks exhibit a range of other quirks, such as the noted insensitivity to physical fitness in early epigenetic clocks, and there is clearly a great deal more work to be accomplished if clocks are to become trusted enough to be used to assess the potential of new approaches to rejuvenation, and thereby guide the direction of research and development.
Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions.
At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice.
Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions.
Work out of Eric Verdin's lab has shown that aging clocks derived from blood cells likely represent the differentiation states of the circulating immune cells.
He had a talk at the Rejuvenation Startup Summit 2022 where he presented their work in identifying a clock that seems to more accurately represent epigenetic changes associate with aging as opposed to those associated with changes in populations of circulating immune cells:
https://youtu.be/QY4tORgM2N4
With aging there is a shift in immune cell populations with a progressive loss of Naive T cells and these Naive T cells are associated with a more 'youthful' epigenetic state. Just tracking changes in the representative populations of immune cells may likely be as informative as a number of the epigenetic clocks that have been developed.
The recent paper using a rat model mentioned in another entry on this site whereby young plasma was injected into the peritoneal cavity uses a Horvath clock. It is not clear to me how well they are controlling for changes in differentiation states of circulating immune cells, but if I recall correctly they are comparing control versus treated. It would be interesting to know if there are increased numbers of Naive T cells in the treated animals or perhaps greater removal of senescent immune cells via intrinsic/extrinsic means. Perhaps the comparison between control versus treated does account for differences in cell populations at an epigenetic level. Phenotypically (and subjectively) the treated rats look remarkably more healthy and there is an increase in average lifespan in the treated group. There is not a great deal difference in maximum lifespan, so, although they are likely 'healthier', they are not really experiencing a profound life extension. It would have been nice in that paper if they would have done functional testing to assess relative changes in physical activity, etc.