Aging can be broadly defined as a gradual decline in function over time; it is one of the most conserved features of living organisms. Mitochondrial dysfunction is a hallmark of aging, but the mechanisms contributing to the disruption of mitochondrial homeostasis are not clearly understood. Now, researchers led by David Sinclair (Harvard Medical School, Boston, MA) report that a disruption of intracellular communication between the mitochondria and nucleus contributes to aging-related mitochondrial dysfunction.

Nuclear–mitochondrial communication is key, as different subunits of the energy-producing oxidative phosphorylation (OXPHOS) system are encoded in the two genomes; failure to coordinate the two impairs the cell's energy supply. Sinclair's group noted that in aging mice, activity of only the mitochondrially encoded components of the OXPHOS system declined (Cell 155, 1624–1638; 2013).

As their search to identify the biochemical underpinnings of this decline progressed, they investigated several molecules known to be associated with aging or lifespan extension. NAD+ is a coenzyme involved in energy production whose concentration declines with age. It controls the activity of SIRT1, an enzyme with an established role in lifespan extension. Sinclair's team next carried out a series of experiments using aging and Sirt1-knockout mice.

When taken together, the experimental results suggest that as the concentration of NAD+ in the nucleus falls with age, SIRT1 activity is reduced, allowing the transcription factor HIF-1a to accumulate. Accumulation of HIF-1a interferes with normal nuclear–mitochondrial communication, leading to declines in mitochondrial OXPHOS subunits and disruption of mitochondrial homeostasis.

Finally, Sinclair's group evaluated whether they could prevent the disruption, restore intracellular communication and, in effect, turn back the hands of time. They administered a precursor of NAD+ to aging mice for 1 week and observed increases in mitochondrial OXPHOS subunits along with reversal of biochemical changes related to aging. After the 1-week treatment period, mice that were 22 months old had health biomarkers (including indicators of insulin resistance, inflammation and muscle wasting) similar to those normally seen in 6-month-old mice. A similar improvement in humans might be a 60-year-old person with muscle tissue of a 20-year-old, according to the researchers. “There's clearly much more work to be done here, but if these results stand, then certain aspects of aging may be reversible if caught early,” said Sinclair in a statement.

Future studies will analyze longer-term outcomes of NAD+ precursor administration, as well as potential applications in treating rare mitochondrial and more common metabolic diseases, such as diabetes.