Abstract
Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age‐related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (−2.5‐year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from −1.6 year/year from 0–9 month to −6.5 year/year from 9–12 month. The GrimAge predictor of human morbidity and mortality showed a 2‐year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.
Highlights
Population aging is an increasingly important problem in devel‐ oped countries, bringing with it a host of medical, social, eco‐ nomic, political, and psychological problems (Rae et al, 2010).Over the last several years, many biomedical approaches to ame‐ liorating aging have been investigated in animal models, and some of these seem able to reverse general aspects of aging in adult mammals based on a variety of physiological measurements (Das et al, 2018; Ocampo et al, 2016; Zhang et al, 2017)
Thymic function in aging depends on the supply of T‐cell progenitors from the bone marrow, which declines in relation to the output of myeloid HSCs with age (Akunuru & Geiger, 2016), the net number of lymphoid precursors does not change with age (Montecino‐ Rodriguez et al, 2019), and migration of T‐cell precursors from the bone marrow appears to depend on thymic function (Haar, Taubenberger, Doane, & Kenyon, 1989)
The TRIIM trial was designed to investigate the possibility of thymus regeneration and reversion of immunosenescent trends in healthy aging men while minimizing side effects and any possible risks
Summary
Population aging is an increasingly important problem in devel‐ oped countries, bringing with it a host of medical, social, eco‐ nomic, political, and psychological problems (Rae et al, 2010). Two volunteers had abnor‐ mally low levels of thymic fat (high TFFF) at baseline, and their TFFFs did not significantly improve with treatment (peak relative changes of +9.6% (p > .3) and +12.4% (p > .2); Figure 3b). Their lack of response was not age‐dependent. On average, trial volunteer epigenetic ages (EAs) were lower than their chronological ages (As) at baseline [(EA‐A)0 < 0, Table 1], epigenetic age was significantly decreased by treatment based on the results of all four epigenetic clocks (Figure 5a–d), with a mean change in EA‐A after 12 months of about 2.5 years (Figure 5e). Comparing the rates of aging regression between 0–9 and 9–12 months showed that, for every age estimator, the rate of aging regression appeared to accel‐ erate substantially with increasing treatment time (Figure 5a–d and Table 1), with a mean slope over all four clocks of −1.56 ± 0.46 years/ year in the first 9 months to −6.48 ± 0.34 years/year in the last 3 months of treatment (p < .005, Figure 5f)
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