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Longevity, the Ultimate Frontier2024-08-05

What is aging?

It is now becoming the common sense consensus that aging is a degradation of the information needed for proper biological function. The DNA gets mutated, the gene expression is altered by epigenetic changes, and as a consequence genes are expressed in a dysregulated way, leading to dysfunction and medical disorders that can become fatal (¹, ²). The DNA mutations cannot be currently reversed (although types of CRSPR may do it in the future), the epigenetic changes can be reversed with the expression of powerful transcription factors (Yamanaka factors), and gene expression itself can be corrected and kept in check by medications, nutrition, and other lifestyle changes, if done early and targeted enough. But these are all downstream things, chasing consequences, a less efficient way of addressing a problem.

Why does aging occur?

A key question to address is why does aging occur in the first place. That is the key upstream issue to solve, that then will take care of all the downstream issues listed above. It presently appears to me, from our own work and from the state of progress in the field, that there are three possible mechanisms. One is accidental damage, wear and tear. That is passive aging. The solution is to try to avoid radiation, chemical, mechanical, and biological damage as best one can. The second type of aging is an evolutionarily programmed slowing of repair after the job of passing your genes is done, and you become obsolete. That is passive-aggressive aging. Having multiple generations of progeny that are staggered over the years may delay that mechanism. The third and most interesting one is the deliberate shutting down of the biological machinery in an adverse environment, a sort of whole body apoptosis, all the way to suicide. That is active aging/death. That is the realm of where mental health can directly affect our longevity, where a good mood, an optimistic outlook, and a youthful self-image can affect a biological “life switch”(³).

Mental health and longevity

The future is bright for increasing lifespan and healthspan. We propose that starting upstream, with mental health and life outlook, solving and optimizing those (³, ⁴), and then working your way down the causal chain, can transform medicine and society.

Footnotes

1. Rangaraju, S. et al. Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality. Elife 4, e08833, doi:10.7554/eLife.08833 (2015). ↩

2. Yang, J. H. et al. Loss of epigenetic information as a cause of mammalian aging. Cell 187, 1312-1313, doi:10.1016/j.cell.2024.01.049 (2024). ↩

3. Rangaraju, S. et al. Mood, stress and longevity: convergence on ANK3. Mol Psychiatry 21, 1037-1049, doi:10.1038/mp.2016.65 (2016). ↩ ↩²

4. Rangaraju, S. et al. Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non-cell-autonomous stress response. Aging Cell 14, 971-981, doi:10.1111/acel.12379 (2015). ↩