Previous research has pointed to the use of caloric restriction—reducing daily average calorie intake with an altered diet—and metabolite supplementation to combat aging. For example, reducing calorie intake by 20-30% has shown to extend lifespan by 20% or more in organisms like mice, flies, fish, and spiders, and we’ve seen supplements like resveratrol used against obesity, rapamycin as an anti-cancer agent, and metformin against diabetes. But we’ve only explored the tip of the iceberg when it comes to which compounds exert anti-aging effects in humans and how they do so.

A recent review from Kondoh and colleagues from Japan in the International Journal of Molecular Sciences explored research on markers of aging in human blood. They focused on an array of metabolites present in the blood during aging to identify age-related disease-associated metabolites. Their analysis of published studies points to 14 small organic compounds generated as metabolic byproducts (metabolites), nine that diminish and five that increase during aging. These findings may improve diagnostics and clinical interventions in age-related diseases.

(Kondoh et al., 2020 | International Journal of Molecular Sciences) Fourteen blood marker metabolites either diminished or increased with age. Nine of the blood metabolite markers for aging diminished, and five of them increased. Five of these 14 blood markers increased in fasting, and five of them diminished in frailty.

Blood Metabolite Markers Overlap in Aging and Fasting

(Kondoh et al., 2020 | International Journal of Molecular Sciences) Fasting and calorie restriction extend the lifespan of experimental animals. During fasting, signaling modules including sirtuin, Tor kinase, and AMPK, become activated or inactivated. Molecules or compounds mimicking caloric restriction (CR) conditions increase longevity in experimental animals, resveratrol for sirtuin, rapamycin for Tor kinase, and metformin for AMPK. Scientists still know little about the effect of fasting and calorie restriction on human longevity.

In their analysis of metabolite profiles, Kondoh and colleagues identified five metabolites that increased with aging. These included metabolites from converting toxic ammonia to a substance in urine called urea along with another urine compound called dimethyl-guanosine. They also identified nine blood metabolite markers that diminish in elderly adults

 Of these, two play roles in muscle maintenance (leucine and isoleucine), two are involved in maintaining electron balance within cells (NAD+ and NADP+), and one is a blood sugar called a sugar mononucleotide (UDP-acetyl-glucosamine).

The remaining four blood metabolites that decreased with aging are antioxidants that combat harmful oxygen-containing molecules called reactive oxygen species (1,5-AG, OA, acetyl-carnosine, and carnosine). They noted that blood metabolite markers of aging include antioxidants, which suggests that oxidative stress can be a key physiological stressor, possibly inducing aging processes. Along those lines, increased antioxidant defense from fasting could moderate aging and age-related diseases.

Of the 14 metabolites that are altered in aging, five have been shown to also be affected by caloric restriction from fasting. This included four of the metabolites that decreased with aging — OA, carnosine, leucine, and isoleucine — and pantothenate, which increased with aging.

(Kondoh et al., 2020 | International Journal of Molecular Sciences) Four reduced blood metabolite markers in aging increase during fasting. Diminished levels of antioxidant ophthalmic acid (OA), carnosine, leucine, and isoleucine represent markers of aging that overlap with increased levels during fasting. OA and carnosine are antioxidants, while leucine and isoleucine play heavy roles in muscle maintenance.

Metabolite Blood Markers Overlap In Aging and Frailty

Five blood metabolites that diminished with aging also did in frailty. This included three antioxidants (1,5-AG, OA, and acetyl-carnosine) and two with significant roles in muscle maintenance (leucine and isoleucine). The identification of blood metabolite markers overlapping in aging and frailty may provide researchers with metabolic targets for supplementation during aging for age-related disease prevention.

(Kondoh et al., 2020 | International Journal of Molecular Sciences) Metabolite blood markers for aging, frailty, and cognitive markers indicate that five markers overlap between aging and frailty. Five blood metabolite markers for aging and frailty overlap. 1,5-AG, acetyl-carnosine, and OA are antioxidants, while leucine and isoleucine play significant roles in muscle maintenance. The antioxidant marker of cognitive impairment acetyl-carnosine also overlaps as a marker for aging and frailty. Supplementing these metabolites during aging may offer researchers a means to reduce the effects of aging and age-related diseases.

“Interestingly, metabolites affected in frailty largely overlap with metabolites that decrease during aging (acetyl-carnosine, OA, 1,5-AG, isoleucine, and leucine) and compounds that increase during fasting (2-ketobutyrate, OA, isoleucine, leucine, urate, and ET) indicating an intriguing metabolic link between frailty and human aging,” stated the researchers in their article. 

Metabolite Blood Markers Provide Insight for Therapeutic Targets During Aging

“As one hint of human aging research, results of whole blood metabolomics help to better understand biological age, especially given the variable nature of aging.” With a greater diversity of factors causing disease in aged individuals, finding common blood metabolite markers predisposing to aging and age-related diseases may provide scientists with therapeutic targets for supplementation.

Research continues on the supplementation of metabolites. For example, nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) may be an intervention against human aging. As NAD+ constitutes one of the diminished metabolites during aging, utilizing NMN supplementation to increase NAD+ may improve overall healthspan during aging. Future metabolomics blood research may point to new supplements to improve metabolite profiles for healthy aging.