Alpha-Ketoglutarate Extends Lifespan and Compresses Morbidity in Aging Mice

As we age, our metabolism — all of the chemical reactions that help keep our body alive — does not operate as well as when we were younger. Our bodies don’t extract nutrients from food and turn them into energy and the building blocks of our cells as efficiently. Also, as we age, the levels of many compounds in our bodies change, such as those for alpha-ketoglutarate (AKG). This key metabolite has been reported to extend lifespan in both worms and flies and act 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 AKG extends the lifespan of middle-aged female mice and increases healthspan in both sexes. With the simultaneous reduction in frailty and an increase in longevity, the intervention compressed morbidity. AKG exerts these effects in part by suppressing chronic inflammation. If translated to humans, this could meaningfully reduce the period of time spent suffering from age-related conditions, increase the period of healthy living, and dramatically reduce the cost of providing healthcare to an aging population.

Can alpha-ketoglutarate aid in increasing longevity in mammals?

AKG is a compound that our bodies make that is involved in various fundamental processes, including central metabolism, collagen synthesis, stem cell proliferation, and regulation of epigenetics — heritable changes that do not involve alterations in the DNA sequence. It stimulates protein synthesis and inhibits protein degradation in muscles, is a central metabolic fuel for cells of the gastrointestinal tract, and can decrease protein breakdown and increase protein synthesis to enhance bone tissue formation in the skeletal muscles.

Due to its broad biological roles, AKG has been a subject of interest for researchers in various fields. Interestingly, in humans, plasma AKG levels are reported to decline 10-fold between the ages of 40 and 80. The molecule is not available in the human diet, making direct supplementation the only feasible route to restore levels.

Supplementing diet extends the lifespan of middle-aged female mice

Here, Shahmirzadi and colleagues investigated the effect of AKG (delivered in the form of a calcium salt, CaAKG) on healthspan and lifespan in mice. To probe the relationship between healthspan and lifespan extension in mammals, they performed a series of longitudinal, clinically relevant measurements.

Their main findings were that a diet supplemented with CaAKG extends the lifespan and healthspan of both female and male mice. But these effects were more pronounced in females. The median lifespan and survival of females were significantly extended from the inception of CaAKG feeding. Although improved survival for males was not significant in either cohort, the median lifespan was extended from the inception of treatment.

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

The reduction in frailty is more dramatic than lifespan extension

Next, Shahmirzadi and colleagues tested the effects of CaAKG treatment on age-dependent features. CaAKG treatment significantly decreased the severity of multiple age-dependent characteristics in females, including skin irritation, gait disorder, and kyphosis -- curving of the spine in a hunchback like manner. In males, the severity of body condition, skin irritation, gait disorder, eye discharge, kyphosis, and tumors were all decreased.

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

Alpha-ketoglutarate keeps chronic inflammation at bay

Shahmirzadi and colleagues next looked into how AKG exerted its effects on healthspan and longevity in both mouse sexes. They observed that AKG reduces chronic inflammation and induces the levels of a secreted molecule called IL-10 by immune cells called T cells of female mice. Notably, female T cells significantly produce higher IL-10 upon AKG treatment. This effect, as well as suppression of inflammation and decreased mortality, were sex-specific. Considering 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 potential mechanism for suppression of chronic inflammation in females.

Better to be generally recognized as safe than sorry

"The study allowed us to document healthspan changes that took place over time, including benefits in reduced frailty, reduced inflammation, and the increased physical activity in the calcium alpha-ketoglutarate group," said one of the trial's senior researchers, Brian Kennedy, Ph.D. "Although the study was conducted on animals, humans share a number of major molecular aging pathways with mice and experience many of the same challenges to health associated with old age," he continued. "We are of the view that supplementation with calcium alpha-ketoglutarate may impact important elements of human aging and improve quality of life in the elderly population," said Dr. Kennedy, Director of the Center of Healthy Ageing of 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 reduced systemic inflammation as a potential longevity mechanism by AKG in females, this mechanism of action is absent in male animals. Also, the researchers were not able to assess cognitive functions and behavior. It has been shown previously that the endogenous AKG levels in plasma decrease upon aging in mice and oral supplementation of AKG can restore levels; however, this wasn’t quantified in the current study.

Nevertheless, since it has been granted GRAS (Generally Recognized As Safe) status by the FDA and human safety record, these findings point to a potential safe human intervention with AKG that may impact important elements of aging and improve quality of life in the elderly population.

References:

Asadi Shahmirzadi A, Edgar D, Liao CY, Hsu YM, Lucanic M, Asadi Shahmirzadi A, Wiley CD, Gan G, Kim DE, Kasler HG, Kuehnemann C, Kaplowitz B, Bhaumik D, Riley RR, Kennedy BK, Lithgow GJ. Cell Metab. 2020 Sep 1;32(3):447-456.e6.