Alpha-ketoglutarate supplementation has been shown to modestly extend life span and improve measures of health in old mice; the publicity materials here accompany the formal release of that paper. Recently, a novel epigenetic clock was used to suggest that alpha-ketoglutarate supplementation in old humans can reduce epigenetic measures of aging, though since this was a novel epigenetic clock, those results should not yet be taken too seriously. Confirming studies are needed, assessing other metrics.
Alpha-ketoglutarate supplementation may act to produce benefits via reductions in excessive inflammatory signaling. Given the sizable influence that the chronic inflammation of aging has on the development of disease and dysfunction, any approach to achieve that goal should be at least in principle interesting. Effect size matters, of course, and here in mice it is both modest and gender-specific, usually signs that effects in humans will be small at best.
Studies show that blood plasma levels of alpha-ketaglutarate (AKG) can drop up to 10-fold as we age. Fasting and exercise, already shown to promote longevity, increase the production of AKG. AKG is not found in the normal diet, making supplementation the only feasible way to restore its levels. AKG is involved in many fundamental physiological processes. It contributes to metabolism, providing energy for cellular processes. It helps stimulate collagen and protein synthesis and influences age-related processes including stem cell proliferation. AKG inhibits the breakdown of protein in muscles, making it a popular supplement among athletes. It also has been used to treat osteoporosis and kidney diseases.
Middle-aged mice that had AKG added to their chow were healthier as they aged and experienced a dramatically shorter time of disease and disability before they died. “The mice that were fed AKG showed a decrease in levels of systemic inflammatory cytokines. Treatment with AKG promoted the production of Interleukin 10 (IL-10) which has anti-inflammatory properties and helps maintain normal tissue homeostasis. Chronic inflammation is a huge driver of aging. We think suppression of inflammation could be the basis for the extension of lifespan and probably healthspan, and are looking forward to more follow up in this regard. We observed no significant adverse effects upon chronic administration of the metabolite, which is very important.”
Many of the study results were sex specific, with female mice generally faring better than males. Fur color and coat condition were dramatically improved in the treated females; the animals also saw improvement in gait and kyphosis, a curvature of the spine often seen in aging. The females also saw improvements in piloerection, which involves involuntary contraction of small muscles at the base of hair follicles. Male mice treated with AKG were better able to maintain muscle mass as they aged, had improvements in gait and grip strength, less kyphosis and exhibited fewer tumors and better eye health.
Here we show that alpha-ketoglutarate (delivered in the form of a Calcium salt, CaAKG), a key metabolite in tricarboxylic (TCA) cycle that is reported to extend lifespan in worms, can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes including collagen synthesis and epigenetic changes. Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields. AKG also influences several age-related processes, including stem cell proliferation and osteoporosis. To determine its role in mammalian aging, we administered CaAKG in 18 months old mice and determined its effect on the onset of frailty and survival, discovering that the metabolite promotes longer, healthier life associated with a decrease in levels of inflammatory factors. Interestingly the reduction in frailty was more dramatic than the increase in lifespan, leading us to propose that CaAKG compresses morbidity.