Investigating SIRT3 as a Target for Calorie Restriction Mimetic Development

Research into sirtuins emerged from research into the sweeping beneficial metabolic changes that take place due to the practice of calorie restriction. The mainstream research community would like to build drugs, calorie restriction mimetics, that reproduce some fraction of these changes with minimal side-effects. This involves first finding key proteins in the mechanisms that coordinate the metabolic reaction to fewer calories in the diet, and then finding or designing compounds that can change the amounts of those proteins.

So far work on sirtuins has largely meant work on sirtuin 1, and this has generated only knowledge. Despite the hopes for activators of sirtuin 1 (overinflated hopes, as is often the case in areas with significant venture capital invested) this looks like a dead end. There is no reliable extension of life shown in animal studies, and doubts are cast on the early consensus of research in this regard. Nonetheless, there is inertia in funding for this line of research and investigations continue.

Some researchers have moved on to look at mTOR and its activators, as there is far better and more reliable data there for life span extension in mice. Even so, there are good reasons not to buy into another hype machine, one that will no doubt wind up for action the moment that a biotech startup in this area obtains meaningful funding. There is no reason to expect any effort involving metabolic manipulation to slow aging to produce good results for human life extension any time soon. These are enormously challenging, enormously expensive efforts, and the payoff is unlikely to be any greater than that produced by moderate exercise or the practice of calorie restriction. This is peanuts in the grand scheme of things, compared to actual rejuvenation of the old, reversal of aging, that might be obtained through a focus on repairing cellular damage rather than altering metabolism to gently slow the rate at which that damage accrues.

But this is the mainstream of longevity science: a comparatively small research community, of which most are focused on a comparatively poor approach to achieving their end goals. So we come to sirtuin 3, which has been gathering more interest in recent years. This sirtuin, unlike sirtuin 1, is a mitochondrial protein. Mitochondria occupy an important place in the roots of degenerative aging, and levels of sirtuin 3 appear to affect mitochondrial function to a great enough degree to influence health and longevity. As you can see from the title of this open access review paper, there is some enthusiasm for work on sirtuin 3. One might expect that this line of research may too at some point in the near future blossom into an overhyped, venture-funded effort to build a calorie restriction mimetic drug worthy of the name:

Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration

Caloric restriction (CR), fasting, and exercise have long been recognized for their neuroprotective and lifespan-extending properties; however, the underlying mechanisms of these phenomena remain elusive. Such extraordinary benefits might be linked to the activation of sirtuins. In mammals, the sirtuin family has seven members (SIRT1-7), which diverge in tissue distribution, subcellular localization, enzymatic activity, and targets.

SIRT1, SIRT2, and SIRT3 have deacetylase activity. Their dependence on NAD+ directly links their activity to the metabolic status of the cell. High NAD+ levels convey neuroprotective effects, possibly via activation of sirtuin family members. Mitochondrial sirtuin 3 (SIRT3) has received much attention for its role in metabolism and aging. Specific small nucleotide polymorphisms in Sirt3 are linked to increased human lifespan.

SIRT3 mediates the adaptation of increased energy demand during CR, fasting, and exercise to increased production of energy equivalents. SIRT3 deacetylates and activates mitochondrial enzymes involved in fatty acid β-oxidation, amino acid metabolism, the electron transport chain, and antioxidant defenses. As a result, the mitochondrial energy metabolism increases.

In addition, SIRT3 prevents apoptosis by lowering reactive oxygen species and inhibiting components of the mitochondrial permeability transition pore. Mitochondrial deficits associated with aging and neurodegeneration might therefore be slowed or even prevented by SIRT3 activation. In addition, upregulating SIRT3 activity by dietary supplementation of sirtuin activating compounds might promote the beneficial effects of this enzyme.

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