Calcium alpha-ketoglutarate extends lifespan and compresses morbidity in aging mice

As we age, our metabolism—all the chemical reactions that keep our bodies alive—doesn't work as well as when we were younger. Our bodies don't get nutrients from food and don't convert them as efficiently into energy and the building blocks of our cells. As we age, the levels of many compounds in our bodies also change, such as those for alpha-ketoglutarate (AKG). This important metabolite has been reported to extend the lifespan of both worms and flies and acts as an antioxidant in mammalian cells. But its role in aging and longevity in mice, let alone humans, is relatively unknown.

Shahmirzadi and colleagues report that a diet supplemented with Ca-AKG extends the lifespan of middle-aged female mice and improves health in both sexes. With the simultaneous reduction in frailty and an increase in longevity and reduced morbidity. Calcium alpha-ketoglutarate exerts these effects in part by suppressing chronic inflammation. Translated to humans, it can significantly shorten the time spent with age-related conditions, extend the period of healthy living, and dramatically lower the cost of providing health care to an aging population. 

 

Can alpha-ketoglutarate help extend lifespan in mammals?

AKG is a compound our body makes and is involved in several fundamental processes, including central metabolism, collagen synthesis, stem cell proliferation and regulation of epigenetics - heritable changes that do not involve changes in the DNA sequence. It stimulates protein synthesis and inhibits protein breakdown in muscle, is a central metabolic fuel for cells of the gastrointestinal tract and can reduce protein breakdown and increase protein synthesis to improve bone tissue formation in skeletal muscle.

Due to its broad biological role, AKG has been a topic of interest for researchers in various fields. Interestingly, in humans, plasma AKG levels are said to drop 10-fold between the ages of 40 and 80. The molecule is not available in the human diet, making direct supplementation the only viable way to restore levels.

Supplemental diet extends the lifespan of middle-aged female mice

Here, Shahmirzadi and colleagues examined the effect of AKG (supplied in the form of a calcium salt (Ca-AKG) on health and longevity in mice. To investigate the relationship between health span and lifespan extension in mammals, they performed a series of longitudinal, clinically relevant measurements.

Their main findings were that a diet supplemented with Ca-AKG prolongs the lifespan and health of both female and male mice. But these effects were more pronounced in women. The median lifespan and survival of females were significantly prolonged from the start of CaAKG feeding. Although improved survival for men was not significant in either cohort, the median lifespan was prolonged from treatment initiation.

In particular, CaAKG administration that started at 18 months of age had robust effects. This is valuable, as clinical studies in humans are likely to start at a similar relative age. If translated to humans, this effect would be highly desirable, extending lifespan but more importantly, shortening the period of functional decline and disease.

 

Reducing vulnerability is more dramatic than extending lifespan

Next, Shahmirzadi and colleagues tested the effects of Calcium alpha-ketoglutarate treatment on age-dependent characteristics. Calcium alpha-ketoglutarate treatment significantly reduced the severity of multiple age-related diseases in women, including dermatitis, gait disturbance, and kyphosis - curvature of the spine in a humpback fashion. In men, body condition severity, dermatitis, gait disturbance, eye discharge, kyphosis, and tumors were all reduced.

They also examined the physical activity and walking ability of these rodents. Interestingly, despite increased locomotion, levels of oxygen consumption, carbon dioxide production and energy expenditure were significantly lower in the CaAKG treated group. Not all functions are improved by Ca-AKG. For example, mice supplemented with Ca-AKG did not perform better in a treadmill exhaustion test and showed no improvement in cardiac function, as determined by echocardiography. Importantly, however, we detected no significant adverse changes with CaAKG treatment.

 

Alpha-ketoglutarate keeps chronic inflammation at bay

Shahmirzadi and colleagues next examined how AKG exerted its effects on health and longevity in both sexes of mice. They noted that AKG reduces chronic inflammation and induces the levels of a secreted molecule called IL-10 by immune cells called T cells from female mice. Notably, female T cells produce significantly higher IL-10 after AKG treatment. This effect, as well as suppression of inflammation and reduced mortality, were sex-specific. Given the critical role of T cell-mediated IL-10 in chronic inflammatory conditions, the researchers believe that induction of IL-10 by AKG treatment is a possible mechanism for suppressing chronic inflammation in women.

CONCLUSION

"The study allowed us to document health span changes that occurred over time, including benefits in reduced frailty, reduced inflammation and the increased  activity in the calcium-alpha-ketoglutarate group," said one of the researchers.
Brian Kennedy, Ph.D. "Although the study was conducted on animals, humans share some important molecular aging pathways with mice and experience many of the same health problems associated with old age," he continued. "We believe that supplementation with calcium alpha-ketoglutarate can influence key elements of human aging and improve the quality of life of the elderly population," said Dr. Kennedy, director of the Center of Healthy Aging at the National University of Singapore.

This study has some limitations and more research is needed to determine how AKG directly affects longevity. While these findings support increased IL-10 and decreased systemic inflammation as a possible longevity mechanism by AKG in females, this mechanism of action is absent in males. Also, the researchers were unable to assess cognitive functions and behavior. It has been previously shown that endogenous plasma AKG levels decrease with aging in mice and that oral supplementation of AKG can restore levels; however, this was not quantified in the current study.

Nevertheless, given that it has been awarded GRAS (Generally Recognized As Safe) status by the FDA, these findings point to a possible safe human intervention with AKG that may affect key elements of aging and improve the quality of life of the elderly.