Modest Life Extension in Mice via CD38 Inhibition

Nicotinamide adenine dinucleotide (NAD) in the context of aging and mitochondrial function has turned into a fairly energetic area of study. NAD is a crucial element in the mitochondrial production of the chemical energy store molecule adenosine triphosphate (ATP), but levels decline with age for a variety of reasons, and this contributes to loss of mitochondrial function. The characteristic changes in gene expression that take place with age lead to reduced production and recycling of NAD via various pathways. Further, CD38 acts to break down NAD and levels of CD38 increase with age.

Why does CD38 production increase with age? Research suggests that this is a consequence of inflammatory signaling, the chronic inflammation of aging, driven in part by a growing burden of senescent cells, but also by molecular damage and debris that triggers similar immune reactions to those produced by infection.

In today's open access paper, researchers report on the effects of partial inhibition of CD38 in mice. In principle, the effect of this inhibition is to disconnect the relationship between inflammation and impaired mitochondrial function mediated by loss of NAD. This disconnection enables improved health and life span. This is an effect likely also possible to achieve via exercise, though not to the same magnitude when it comes to gains in maximum life span; in mice exercise only improves healthspan and medial life span.

Mouse lifespan is more plastic than that of humans in response to interventions that improve metabolism. It isn't clear at this point as to whether a 10-20% increase in lifespan should be seen as interesting. I am starting to lean towards reversal of age-related pathology in later life as a more interesting metric. Regardless of my opinion, clearly there will be considerable further effort devoted towards the clinical translation of ways to increase NAD levels or interfere in the activities of CD38. We shall see how well it does in humans at the end of the day, with structured exercise programs as the bar to beat.

CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging

NAD is a cofactor of oxidation-reduction reactions and is a substrate for enzymes involved in cellular homeostasis. NAD levels decrease with aging and progeroid states, which is associated with metabolic abnormalities and fitness decline. The NAD-consuming enzymes such as CD38 and PARP1 have been shown to play a major role in this process. The accumulation of CD38+-inflammatory cells decreases NAD levels in aging. The small molecule 78c is a specific and potent inhibitor of CD38 that boosts NAD levels, improves survival of progeroid mice, and ameliorates several metabolic, structural, and molecular features of aging. However, to date the effect of CD38 inhibition on natural aging and longevity has not been explored. Here, we demonstrate that 78c increases the lifespan and healthspan of naturally aged male mice.

When offered the food to young mice ad libitum, 78c significantly boosted NAD, validating the 78c treatment. We then placed 1-year-old C57BL/6 male and female mice on either a control or 78c diet and closely followed their healthspan and longevity. When both sexes were grouped, treatment with 78c significantly improved longevity, with a maximal survival increase of 9%. When analyzing survival for males and females separately, a sex-specific effect of 78c was observed. The 78c-treated males had a 17% increase in median survival and a 14% increase in maximal lifespan compared with control. In females, no significant survival benefit was observed

We then evaluated the effect of 78c on the frailty in a cohort of old male mice. Frailty scores were derived from clinical examination. Changes in frailty index after 3 months were plotted in comparison with the baseline index. All animals in the control group had a significantly higher frailty index than that was 3 months earlier. By contrast, 78c showed a protection against age-related frailty increase.


Hello. Thanks. So will a product like this eventually require fda type approval, or be limited to prescription only usage, or will folks like Alex Jones be able to sell it?

Posted by: JBP at March 28th, 2022 6:31 PM

Like previously, CD38 inhibition also decreased body weight, which is probably the mechanism of life span extension, as laid out "Rodent diet aids and the fallacy of caloric restriction".

Posted by: Alexander M. Wolf at March 29th, 2022 11:46 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.