One of the more surprising findings is the existence of a SIRT1-mediated pathway that regulates mitochondria independently of PGC-1α/β. The data indicate that SIRT1 can regulate these two pathways in response to the energetic state of the cell. Which one predominates depends on AMPK activity and the phosphorylation status of PGC-1α (Cantó et al., 2009).
This study shows that HIF-1α-induced metabolic reprogramming occurs in normal tissue and that it disrupts mitochondrial homeostasis. We consider the metabolic state of the old mice as pseudohypoxic because the downstream effects are similar to hypoxia but occur even when oxygen is abundant, as previously in type 2 diabetes and cancer (Ido and Williamson, 1997, Rodgers et al., 2005, Williams and Day, 2003). An interesting implication is that reprogramming of normal tissue toward a Warburg-like state may increase ROS and establish a milieu for subsequent mutations to initiate carcinogenesis, a possibility that may help explain why cancer risk increases exponentially with age.
All of the main players in the nuclear NAD+-SIRT1-HIF-1α-OXPHOS pathway are present in lower eukaryotes, indicating that the pathway evolved early in life’s history. This pathway may have evolved to coordinate nuclear-mitochondrial synchrony in response to changes in energy supplies and oxygen levels, and its decline may be a conserved cause of aging. In C. elegans, HIF-1α is known to be a key determinant of lifespan, though its precise role is still a matter of debate (Leiser and Kaeberlein, 2010). HIF-1α modulation may have differential effects on lifespan depending on the animal’s diet or whether the mtUPR is activated (Dillin et al., 2002, Durieux et al., 2011, Houtkooper et al., 2013). Though we did not detect mUPR in skeletal muscle, we do not exclude the possibility that mtUPR plays a role in other tissues or under different conditions.
Additional studies will be required to elucidate complex feedback loops that likely regulate the SIRT1-HIF-1α-Myc-TFAM pathway. For example, in cancer cells, SIRT1 directly regulates c-Myc transcriptional activity, either by deacetylation of c-Myc (Menssen et al., 2012) or by binding c-Myc and promoting its association with Max (Mao et al., 2011). Given that SIRT3 and SIRT6 also regulate HIF-1α and compromise respiration (Bell et al., 2011, Finley et al., 2011, Zechner et al., 2010), it will be interesting to test whether a decline in the activity of other sirtuins causes a similar loss of TFAM and mitochondrially encoded OXPHOS components.
How broadly applicable might these findings be? High-fat diet feeding increases levels of HIF-1α in liver (Carabelli et al., 2011) and white adipose tissue, the latter of which correlated with a decline in mitochondrial gene expression (Krishnan et al., 2012). Moreover, insulin-resistant human skeletal muscle has a signature reminiscent of hypoxia (Ptitsyn et al., 2006). In SIRT1 iKO mice, specific dysregulation of mitochondrial OXPHOS genes is also observed in the heart, demonstrating that the pathway is relevant not only to skeletal muscle (Figure S1K–S1N), but not in liver, WAT, or brain. In these tissues, other factors such as SIRT3 or SIRT6 may be responsible for regulation of HIF-1α, or the metabolic status of the tissue at the time of harvest may also be critical. Current dogma is that aging is irreversible. Our data show that 1 week of treatment with a compound that boosts NAD+ levels is sufficient to restore the mitochondrial homeostasis and key biochemical markers of muscle health in a 22-month-old mouse to levels similar to a 6-month-old mouse. Although further work is necessary, this study suggests that increasing NAD+ levels and/or small compounds that prevent HIF-1α stabilization or promote its degradation might be an effective therapy for organismal decline with age. In summary, these findings provide evidence for a new pathway that controls carbon utilization and OXPHOS independently of PGC-1α, a pathway that goes awry over time but is readily reversible, with implications for treating aging and age-related diseases.