Epigenetic Rejuvenation (2)

Dreams of Perpetual Youth

The first assumption behind epigenetic rejuvenation is that of all the hallmarks of aging, including telomere shortening, protein misfolding, mitochondrial disfunction, cellular senescence and stem cell depletion, epigenetic alterations are the main drivers. (I discuss theories of aging here, here, here, here).

The second assumption is that aging is not inevitable but rather more like a disease that can be cured. This is the position of David Sinclair, for example.

The third assumption is that we can control the degree to which the epigenetic state of the elderly can be reset to a more youthful state. This is called partial epigenetic reprogramming.

The first assumption is simplistic, the second utopian. The third assumption though, is interesting and testable. It is also the key goal of epigenetic rejuvenation. We already know that the epigenetic clock can be completely reset, as occurs during cloning and in the creation of induced pluripotent stem cells. IPSCs are the point of reference here. We know that they can be created by a cocktail of four or five biochemicals, called Yamanaka factors. But IPSCs were not the hoped for panacea. They differ in important ways from embryonic stem cells. Of most practical importance for rejuvenation research, IPSCs are prone to mutations, cancers and teratomas.

So most epigenetic rejuvenation research is directed toward resetting to a state far short of that of IPSCs, one that preserves the cell phenotypes of a neuron or hepatocyte, but which eliminates any epigenetic modifications subsequent to full differentiation, which are assumed to be aging-related.

One strategy is to use the IPSC cocktail but for shorter timespans, before “the point of no return”, that is, the point at which a neuron is no longer a neuron. The first studies to employ this strategy were conducted in vitro. The results were promising (PMC3088088). The next step was to extend research on the rejuvenating effects of the Yamanaka cocktail to live mice. The mouse subjects of the first such study had been specifically bred to age prematurely, a condition called progeroid. A substantial reversal of physiological decline was reported (27984723), including cardiovascular improvement and increased muscle mass. Crucially, the mice were not adversely affected by the. No signs of cancer etc. The safety of the cocktail was emphasized by the authors.

But what about mice that age normally? This is important because other studies found only transient rejuvenation as the reprogrammed cells reverted to their previous epigenetic selves over time (10.1038/s41467-024-46020-5 ), or induced chromosomal abnormalities over the long term (PMC6076311). So it was important to test for rejuvenation on a mouse model that could be monitored over the longer term.

The first study of this sort used several protocols, of varied dose and length of exposure to the Yamanaka factors (10.1038/s43587-022-00183-2). Consistent with the progeroid mouse study, all protocols were determined to be safe, that is, without the drawbacks of carcinogenesis and elevated mutation rates reported in some previous studies. With respect to efficacy, however, the protocols varied. Those mice exposed the longest to the Yamanaka factors evidenced more rejuvenation than those exposed for lesser time periods. The rejuvenation benefits were manifest in several different organs, including kidneys and skin. There was a significant correlation between the measures of rejuvenation and measures of epigenetic clock resetting, as measured by DNA methylation. But a relatively new biological clock was also used to measure age reversal, which I will consider at more length in the next post, along with attempts to move beyond the Yamanaka factors in epigenetic rejuvenation research.