Longevity

Rapamycin’s Improvement of Muscle Cell Metabolic Balance May Enhance Longevity

A study from UPenn scientists shows rapamycin prevents age-related alterations of metabolic state in muscle cells, which may extend lifespan.

(selvanegra | iStock)
By Bennett M. Sherman

For our cells to function, they require energy generated by transferring electrons through a series of metabolic steps. To maintain this essential energy-producing process, electrons bind to a vital molecule for cellular metabolism called nicotinamide adenine dinucleotide (NAD+) to convert it to NADH. However, as we age, the levels of electrons and NAD+ to NADH ratio become imbalanced disrupting the cell’s homeostasis—the maintenance and regulation of the stability and constancy needed for cells to function properly. These changes may play crucial roles in metabolic dysfunction that facilitate age-related diseases.

Baur and colleagues from UPenn published a study in Aging suggesting rapamycin treatment prevents reduced NAD+ to NADH ratios in mouse muscle. These finds suggest that rapamycin favors a higher NAD+ to NADH ratio and improves energy production. This study provides new insight into how rapamycin might influence the aging process and suggests that NAD+ to NADH imbalances may be an indication that can be targeted using rapamycin to improve health and longevity among the aging population.

How Does Rapamycin Extend Experimental Animal Lifespan?

Research has shown that rapamycin administration extends lifespan in organisms from yeast to mice and could promote healthy aging in humans. So, Baur and colleagues wanted to test the effects of rapamycin on the NAD+ to NADH ratio to better understand how rapamycin promotes lifespan. Previous research pointed to rapamycin reducing production of the metabolite lactate—a substance that turns food into energy—that also facilitates the reduction of NAD+ to NADH. By diminishing lactate production, rapamycin may inhibit converting NAD+ to NADH and prevent potential lactate-induced NAD+/NADH electron imbalance. Perhaps rapamycin reducing lactate production has some effect on the electron balance NAD+ to NADH ratio, which could translate to enhanced longevity. 

Rapamycin Improved Mouse Muscle Cell NAD+/NADH Ratio

The researchers used myoblasts—mouse embryonic precursors of muscle cells that develop into muscle cells—to test whether rapamycin treatment increased the NAD+ to NADH ratio (NAD+/NADH). Long-term cell growth of myoblasts in laboratory dishes (cell culture) with 100 nM concentrations of rapamycin significantly increased NAD+/NADH and diminished NADH levels. Since their results indicated NAD+ levels themselves don’t change with rapamycin treatment, Baur and colleagues found that the NAD+ to NADH level changes were due to NADH level reductions.

(Zhang et al., 2020 | Aging) Rapamycin treatment increased the NAD+/NADH electron balance in muscle cells by reducing NADH concentrations. The left figure (A) shows rapamycin treatment increased the electron balance ratio NAD+/NADH at 48 hours of incubation and further increased the ratio at 72 hours of incubation. The right (C) shows rapamycin treatment facilitated increased electron balance ratios in more developed (differentiated) muscle cells.

Rapamycin Promotes Cellular Production of Energy

Within the mitochondria, cell structures that produce energy carrying molecules called adenosine triphosphate (ATP), NADH donates electrons to an ATP generating enzyme. ATP is a direct cellular energy source and is responsible for a wide variety of cellular activities, including cell proliferation, metabolism, and survival.

As such, Baur and colleagues considered that rapamycin treatment’s reductions in NADH could decrease cellular ATP production, but their results showed otherwise. Rather, ATP concentrations increased in myoblast and myotube cells following one day of rapamycin treatment to cultured cells. The researchers proposed that a rapamycin-induced reduction in cell energy demand may explain the ATP level elevations.

(Zhang et al., 2020 | Aging) Rapamycin treatment increased cell energy molecule ATP levels in embryonic precursor muscle cells and more developed (differentiated) muscle cells. The left figure (A) shows rapamycin treatment increased cell energy molecule ATP levels in embryonic precursor muscle cells (myoblasts). The figure on the right (B) shows the same results for more differentiated muscle cells (myotubes).

Rapamycin Improved Mouse Leg Muscle Metabolic Imbalance

To find whether the mouse muscle cell results translated to a whole organism, the scientists looked at aged mouse leg muscles. They treated the aged mice (17 months old) twice with 2 mg/kg injections of rapamycin before using an imaging technique to evaluate rapamycin’s effects on the NAD+/NADH ratio. Baur and colleagues found no significant differences with treatment in a marker indicative for NAD+ levels (Fp) but found reduced NADH and increased levels of a marker indicating higher NAD+/NADH.

(Zhang et al., 2020 | Aging) The electron balance indicator NAD+/NADH ratio showed rapamycin treatment improved the electron balance that declines with age in mouse leg muscles. The left figure shows no significant changes in levels of a marker indicative of NAD+ levels after rapamycin treatment. In the middle, the graph illustrates that NADH levels diminished with rapamycin treatment, which facilitated the increased NAD+/NADH ratio shown on the right.

“Interestingly, in the present study, we found significant increases in both NAD+/NADH ratio and ATP content in long-term cultured C2C12 myoblasts and myotubes after rapamycin treatment,” stated the researchers in their publication. “This suggests that energetic demand is decreased in the presence of rapamycin, rather than the capacity for ATP synthesis.” Collectively, the results suggest that rapamycin doesn’t suppress mitochondrial ATP production but rather that it reduces the demand for ATP that gets depleted in energy-consuming pathways.

Future Research to Uncover How Rapamycin Promotes Longevity

“This study provides new insight into the mechanisms by which rapamycin might influence the aging process to improve health and longevity among the aging population,” said the authors. Further studies will need to elucidate how rapamycin promotes reductions in cellular energy consumption. Although the study provides a limited idea of how rapamycin may influence the aging process, it suggests that rapamycin may target metabolic imbalances to improve health and longevity in aging individuals. Future research is needed to see if rapamycin similarly exerts its anti-aging effects in humans.

Source

Zhang Z, Xu HN, Li S, Jr AD, Chellappa K, Davis JG, Guan Y, Frederick DW, Chu W, Zhao H, Li LZ, Baur JA. Rapamycin maintains NAD+/NADH redox homeostasis in muscle cells. Aging (Albany NY). 2020 Sep 22;12(18):17786-17799. doi: 10.18632/aging.103954. Epub ahead of print. PMID: 32960787; PMCID: PMC7585102.

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