Longevity

Mayo Clinic Finds That Inhibiting NAD+ Breakdown Increases Lifespan and Prevents Age-Related Physical Decline in Mice

A new study shows that blocking NAD+ breakdown by inhibiting CD38 – an immune system enzyme associated with aging – with a drug called 78c improves longevity and multiple health conditions in mice.

By Daniel R. Miranda, Ph.D.

Key Points: 

  • The CD38 inhibitor 78c increases the longevity of male but not female mice. 
  • The age-related decline in exercise performance is prevented by 78c in the diet. 
  • Feeding mice 78c improves several age-related conditions and increases NAD+ levels in multiple organs. 

NAD+ (nicotinamide adenine dinucleotide) declines with aging in parallel with the health of our cells and organs, eventually leading to age-related disease. A key mediator of NAD+ decline is CD38, an enzyme that increases with age and breaks down NAD+. A new study suggests that we can improve age-related conditions and restore health by inhibiting CD38

In a short communication published in Aging Cell, Peclat and colleagues from the Mayo Clinic demonstrate that 78c increases the lifespan of naturally aged male mice. This research, which comes from the lab of CD38 and NAD+ expert Dr. Eduardo N. Chini, also shows that 78c improves many areas typically affected by aging, including improved exercise performance, endurance, and metabolic function. Furthermore, they show that 78c treatment raises NAD+ levels in multiple organs. These findings suggest that inhibiting CD38 with 78c could prevent many age-related conditions and increase longevity. 


(Peclat et al., 2022 | Aging Cell) Mice Fed 78c Live Longer and Have A Longer Healthspan.  Mice fed the CD38 inhibitor 78c live longer and have a longer healthspan (improvement in health indicators like strength, exercise performance, metabolic activity, and frailty). 

Inhibiting CD38 with 78c Increases Survival Rate of Mice 

The small molecule 78c inhibits CD38, resulting in elevated levels of NAD+ – a vital molecule involved in sustaining the metabolic balance of our cells. CD38 is an enzyme that increases with age in response to inflammation and breaks down NAD+. Blocking CD38 improves the survival of prematurely aged mice and several aging features. However, the effect of CD38 inhibition on natural aging and longevity has not been explored until now. Peclat and colleagues are the first to study the impact of CD38 inhibition on mice throughout their lifespan.

To study the effect of inhibiting CD38, the Mayo Clinic scientists fed mice a diet where 78c was mixed into the food. The mice were monitored throughout their lifetime to determine how long they would survive. When the data from both male and female mice were grouped together, treatment with 78c increased longevity by 9%. This would be about a 7-year increase in lifespan for humans.

Interestingly, when analyzed separately, males had a 14% increase in longevity and females had no increase in longevity. It’s unclear what the effect of 78c was on female longevity because some female mice had such severe adverse reactions to 78c that many were euthanized before dying of natural causes. Up until the point of euthanasia, the female mice treated with 78c had an increase in longevity. So, while 78c safely increased longevity in some females, this treatment caused major side effects in others.

78c Prevents Age-Related Decline in Exercise Performance 

While monitoring the 78c treated mice across a lifespan, Peclat and colleagues evaluated exercise performance at several different time points. The control mice showed a faster age-related decline in maximum distance run than those treated with 78c. These findings indicate the exercise performance declines with age in mice and can be prevented by inhibiting CD38 with 78c. 


(Peclat et al., 2022 | Aging Cell) Longevity and Exercise Performance Improved by CD38 Inhibitor 78c. (left) Mice treated with 78c live longer than mice not treated with 78c. (middle) The age-related decline in running distance is prevented by 78c. (right) Decline in running distance at 50 weeks (on 78c drug) compared to 28 weeks is prevented by treatment with 78c.  

78c Relieves Aging Symptoms & Boost NAD+ 

Peclat and colleagues also dug into the effects of 78c on several aspects of age-related health. For example, since muscle strength tends to decline with age, they assessed grip strength by measuring how long mice could hang from a bar. The mice treated with 78c hung for longer durations, suggesting that 78c improves muscle strength. We tend to lose strength because we lose muscle, and, at the same time, we gain fat and become more sedentary. The 78c-treated mice had a lower percentage of body fat and a higher percentage of muscle, and were more active, especially at night. These findings suggest that inhibiting CD38 with 78c could prevent these harmful consequences of aging. 

In a group of old male mice treated with 78c, Peclat and colleagues evaluated frailty and insulin sensitivity – cells’ ability to uptake glucose, the decline of which leads to diabetes. The 78c treated mice were less frail and had improved insulin sensitivity compared to the old male mice not given 78c. Insulin sensitivity in the old mice was restored back to the level of young mice. With age, frailty increases and insulin sensitivity decreases in humans, so these findings suggest that 78c can prevent such age-related conditions. 

To verify that 78c promoted an increase in NAD+ levels by inhibiting CD38, the researchers measured NAD+ levels in several different organs from the old male mice. They found that NAD+ levels were boosted in the liver, spleen, heart, and intestines of the mice treated with 78c. While not all organ systems were examined in the study, these findings suggest that 78c leads to a body-wide boost in NAD+.

Because senescent cells – stressed-induced growth-arrested cells – are associated with activating CD38 and depleting NAD+, Peclat and colleagues measured senescent markers in the old male mice. Surprisingly, the researchers did not find any changes in the senescent markers. This suggests that boosting NAD+ at a later age reduces aging through mechanisms other than decreasing senescence. Understanding these mechanisms will require further investigation. 


(Peclat et al., 2022 | Aging Cell) 78c Prevents Age-Related Decline of NAD+ in Multiple Organs. Treating old male mice with 78c prevents NAD+ from declining in the liver, spleen, heart, and intestines (jejunum). 

Too Good to Be True?

If 78c, this CD38 inhibitor sounds too good to be true, some people might like it to be. The senior author of this study holds patents for CD38 inhibitors licensed by Elysium Health. He also consults for the drug developing companies Calico, Mitobridge, and Cytokinetics. This doesn’t mean that there is anything wrong with the science, but it would be good to have other researchers without stakes in CD38 inhibitors come up with similar results in their own studies. 

This is not to say that everything went perfectly in this study. The fact that many of the female mice had to be euthanized suggests that there could be major side effects in humans, especially females. If this can be worked out, we can focus on the positive for now. Peclat and colleagues checked for tumor growth and didn’t find any in the 78c treated mice, which is a good sign because CD38 increases the risk of tumor growth.

Overall, inhibiting CD38 with 78c was shown to raise NAD+ levels, increase longevity, and improve exercise performance, grip strength, body composition, activity levels, frailty, insulin sensitivity, and more. Again, if the side effects could be worked out, this study makes it seem like 78c is some sort of miracle drug. Other studies have also shown that boosting NAD+ in mice increases lifespan. Feeding mice the NAD+ precursor, nicotinamide riboside (NR) increased their lifespan by 5%. Injecting mice with eNAMPT, an enzyme that leads to the synthesis of NAD+ doubles lifespan

Source

Peclat TR, Thompson KL, Warner GM, Chini CCS, Tarragó MG, Mazdeh DZ, Zhang C, Zavala-Solorio J, Kolumam G, Liang Wong Y, Cohen RL, Chini EN. CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell. 2022 Mar 8:e13589. doi: 10.1111/acel.13589. Epub ahead of print. PMID: 35263032.

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