Fight Aging!

Progeria, caused by loss of function mutations in the lamin A gene, is not accelerated aging. It is an example to demonstrate that many forms of cellular damage and disarray, when present to a greatly exaggerated degree, can in some ways mimic manifestations of aging. Aging is, after all, a process of cellular damage and disarray. It is, however, a specific balance of various forms of damage. Change that balance radically, or employ other forms of damage, as is the case in progeroid mice, and the outcome can no longer be called aging. It becomes a challenge to determine whether interventions that help ameliorate the harms of progeria would help meaningfully with normal aging; that depends strongly on the details of each case.

There is a growing interest in applying cellular reprogramming as an in vivo treatment. The goal is to deliver enough of the reprogramming factors to make a significant number of cells become more functional, by improving mitochondrial function and reversing a range of age-related epigenetic changes, but without forcing cells to abandon their roles to become induced pluripotent stem cells. A small number of such conversations is probably acceptable, given the outcome of stem cell therapies, but at some point too much of that will produce cancer or outright tissue failure. Thus initial explorations of reprogramming as a therapy are focused on short or otherwise limited exposure to the reprogramming agents.

A single short reprogramming early in life improves fitness and increases lifespan in old age

In 2006, it was shown that mouse somatic cells can be converted into pluripotent cells (iPSCs) by inducing the expression of four transcription factors: OCT4, SOX2, KLF4, and c-MYC (OSKM). This process of cellular reprogramming induces a global remodeling of epigenetic landscape to revert cell identity to a pluripotent embryonic-like state. Exploiting cell reprogramming offers an alternative route for cell therapy to restore organ and tissue function. Somatic cells can be reprogrammed into iPSCs, then modified or corrected in vitro before being re-differentiated into cells, tissues or organs for replacement in the donor or an immune-compatible patient.

Previous experiments using a reprogrammable mouse model demonstrated that a cyclic induction of OSKM two days a week, over the entire extremely short lifetime of a homozygous accelerated aging mouse model, increased longevity, through a potential chronically unstable epigenetic remodeling. These mice have a mutated Lmna gene that produces high level of the natural aging protein progerin.

In this study, we investigate a single short period of in vivo OSKM induction as pre-clinical proof of principle for a potential usage in clinic to prevent aging defects. We focused on heterozygous animals, which have moderate lifespan and levels of progerin, as these heterozygotes might be extremely sensitive to anti-aging therapies. As a short OSKM induction, was described to ameliorate immediate tissue regeneration after experimentally induced tissues injuries, we wondered whether a short period of OSKM genes induction might improve lifespan and tissues aging of heterozygotes mice.

Surprisingly, we found that many health measures, and longevity itself, were ameliorated in elderly mice, by a single two and a half weeks treatment earlier in life, at two months of age. This outcome was associated with a differential DNA methylation signature, suggesting that a "memorized effect" initiated by our short induction protocol early in life might be involved in a more juvenile physiology.