Sirtuins and the consequences of the age-related NAD+ decline

Sirtuins and the consequences of the age-related NAD+ decline

The combination of decreased biosynthesis and increased breakdown of NAD+ exacerbates its depletion, causing a variety of age-associated conditions and diseases. Which one — an insufficient generation or overstimulated consumption — contributes further to the shortage of NAD+ may depend on cell types and tissues. No matter what causes NAD+ decline, it seems that major downstream mediators are sirtuins.

In humans, the sirtuin family is composed of seven members (SIRT1-SIRT7), all of which play a role in several cellular metabolic processes related to healthspan and longevity. Generally, sirtuins remove a modification called acetylation from target proteins to regulate reactions associated with vital processes such as metabolism, DNA and cellular repair, stress responses, circadian rhythm, and other cellular processes. By mediating such broad functions, sirtuins are evolutionarily conserved regulators for aging and longevity in diverse organisms. 

These various NAD+-dependent functions of sirtuins place them in a key position for regulating aging and longevity in diverse organisms. For example, mice that generate more SIRT1 than typical brains see delays in aging and extended lifespans. Similarly, SIRT1 activation has therapeutic potential in neurodegenerative diseases like Huntington’s disease and amyotrophic lateral sclerosis (ALS). Also, mice that generate more SIRT6 throughout the body show lifespan extension.

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