Sirtuins Remain an Active Area of Research in Aging

Sirtuins are connected to the upregulation of cellular stress response mechanisms triggered by, for example, calorie restriction. Given the failure of past attempts to intervene in aging at the point of sirtuin 1, it may be that the influence of sirtuins on the pace of aging simply isn't large enough to be useful. That said, work on other sirtuins, such as sirtuin 6 and to a lesser degree sirtuin 3, have produced somewhat better results in mice. Still, stress response upregulation as a whole is demonstrably far more influential on life span in short-lived species such as mice than it is in long-lived species such as humans. Calorie restriction can extend maximum life span in mice by 40%, but certainly does no such thing in humans. This should tell us that we must look elsewhere for means of extending the healthy human life span by decades.

Sirtuins may counteract organismal aging by altering the pattern of cellular stress response to generate much less disruption of tissue homeostasis. The alteration of cellular stress response pattern by sirtuins comprises (1) inhibition of apoptosis, (2) promoting DNA damage repair instead of apoptosis or induction of cellular senescence, (3) antioxidative action through activation of MnSOD, (4) preventing carcinogenesis through acting as tumor suppressor proteins, (5) inhibition of unnecessary inflammatory response/inflammaging through inactivation of NF-kB, and (6) preventing cellular senescence and senescence-associated secretory phenotype (SASP) through mitochondrial protection and promoting DNA damage repair.

All the effects listed above combined may prevent disruption of tissue homeostasis - directly responsible for organismal aging in vertebrates while being itself a distant derivative of a prolonged, inappropriate pattern of cellular response to accidental damage of the biostructure. The mechanisms discussed in this review describe how exactly sirtuin-dependent modifications of the cellular stress response can slow down aging at the tissue level. Thus, sirtuins, especially SIRT1, SIRT3, and SIRT6, can modify cellular stress response to promote maintenance of tissue homeostasis and thus slow down phenotypic aging at the organismal level.



Where should we be looking, longer term. Your idea of aggressively going after arteriosclerosis is a very good idea, and I really hope you can pull it off. Maybe that could pole vault us over to the next big idea.

However, what technology might that be? Seems like the very big problem is that cells accumulate random genetic flaws as they age & divide. Sinclair downplays this & says all that is required is an epigenetic tuning. The trouble is.. can these cells really be targeted in any consistent way? The immune system can target all sorts of problematic cells. But could it ever target all non mutated cells? Seems impossible. What do you think?

Of course maybe we could get good at replacing stem cells. Then we'd just need to from time to time kill off cells at a rate that is > their self mutation rate. Then add very healthy, non-mutated stem cells into the proper locations... and let natural cell programming handle replacing cells.

Curious what your tip top best ideas for extending lifespan are. I've been reading / studying for just a couple years now & it seems like the best ideas are: your arteriosclerosis fix, organ growth / replacement, senescent cell clearance, CMA rescue, engineered, forever young stem cells, mitochondrial boosting, maybe epigenetic reprogramming.

Posted by: Matt at December 24th, 2021 4:55 PM

As my birthday is last day of the year, I have always treasured your (Reason's) yearly update in the longevity field at year end (er maybe it was beginning of year).

Posted by: Robert at December 24th, 2021 8:08 PM
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