Note in Science page
Created Jan 10 14, Updated Jan 10 14 18:07
Age related mitochodrial disfunction might be reversible go to comments

New [And Reversible] Cause of Aging: Naturally Produced Compound Rewinds Aspects of Age-Related Demise in Mice

Researchers found that by administering an endogenous compound that cells transform into NAD, they could repair the broken network and rapidly restore communication and mitochondrial function.
If the compound was given early enough (prior to excessive mutation accumulation) within days, some aspects of the aging process could be reversed.


Nicotinamide mono nucleoside (NMN), © sigmaaldrich.com

Original research paper:
Declining NAD Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging. Cell, 2013; 155 (7): 1624 DOI: 10.1016/j.cell.2013.11.037

Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1?/?-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD+ and the accumulation of HIF-1? under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1?/?-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible. (Cell paper abstract)

Treatment of 22-month-old mice for 1 week with [Nicotinamide mono nucleoside] NMN, a precursor to NAD+ that increases NAD+ levels in vivo ... reversed all of these biochemical aspects of aging and switched gastrocnemius muscle to a more oxidative fiber type. However, we did not observe an improvement in muscle strength (data not shown), indicating that 1 week of treatment might not be sufficient to reverse whole-organism aging and that longer treatments might be required.

For NMN experiments, mice were given IP injections of 500 mg NMN/kg body weight per day or the equivalent volume of PBS for 7 consecutive days

p.s. another NAD+ inducing component, part of a NAD+ salvage pathway: Nicotinamide Riboside (some suggest that NR may be the only NAD precursor that supports neuronal NAD+ synthesis, and is more potent than vitamin B3:nicotinic acid/nicotinamide)


Nicotinamide Riboside (NR)

p.s. NR is converted to NMN by ribosylnicotinamide kinase in (some!) target tissues. NR can be taken orally and is commercially available

p.s. the huge dose of 500 mg NMN/kg /day on mice, with allometric scaling from mouse to human (/12) would correspond to ~40mg/kg / day on human … Studies on NR where using 450 mg/kg /day (oral) doses…


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