Telomere dysfunction has been linked to many aspects of the ageing process. Genetic model systems have established the essentiality of preserved telomere function in the regenerative maintenance of highly proliferative organs as well as in the preservation of physiological functions of more quiescent organs such as heart, brain and liver. Although classical p53-directed checkpoints of proliferative arrest and apoptosis have provided a strong basis for atrophy and functional impairment of high turnover tissues, the mechanistic basis for comparably severe compromise of less proliferative tissues has been an enigma. Here, combined transcriptomic, molecular, genetic and functional analyses on cellular and organismal levels established a direct molecular link between telomere dysfunction and repression of PGC-dependent processes of mitochondrial biogenesis/function, gluconeogenesis and oxidative defence. This combined repression of PGC-1α and PGC-1β and associated decline in mitochondrial biogenesis and function as well as metabolic changes aligns well with the phenotypes elicited by combined PGC-1α and PGC-1β knockdown in vitro
or knockout in vivo25,32
. We propose that telomere dysfunction-induced repression of the PGC network and consequent mitochondriopathy and metabolic changes, along with telomere-induced apoptotic and proliferative checkpoints, contributes to functional multi-system decline in the setting of telomere dysfunction.
Given the diverse roles of PGC in multiple biological processes, the relative contribution of each of the dysregulated PGC arms to functional decline in the setting of telomere dysfunction may differ in various tissue types. For example, the PGC-directed mitochondrial dysfunction might be particularly critical in heart, whereas changes in metabolic gene expression may predominate in liver. Of potential clinical interest is the link of PGC to insulin resistance and diabetes in ageing, both of which are correlated with short telomeres33,34
. These mitochondrial and metabolic aspects of telomere-driven pathophysiology are not mutually exclusive with the well documented ‘DNA damage’ checkpoints associated with telomere dysfunction. These DNA damage checkpoints manifest primarily as cellular senescence and/or apoptosis which contribute to depletion and compromise of tissue stem cell reserves, particularly in highly proliferative organs such as intestine, skin and blood13,35,36
. Although the relative contributions of these checkpoints versus metabolic/mitochondrial dysfunction in a given degenerative phenotype will require further study, the latter mechanism may explain the profound physiological impairment observed in the more static, post-mitotic tissues such as heart (cardiomyopathy) and liver (impaired gluconeogenesis), leading to feeble energy stress responses and overall frailty due to a fundamental inability to produce adequate cellular ATP. As with other mitochondriopathies, this mitochondrial defect in the setting of telomere dysfunction becomes increasingly apparent under conditions of physiological stress or advanced age2
. Whereas the instigator of decline in advanced age is not known, our findings raise the possibility that the well-known phenomenon of accelerating physiological decline in the aged could stem from a primary decline in PGC/mitochondrial function which in turn would lead to increased ROS, resulting from the diminished OXPHOS/complex activity and decreased expression of PGC-regulated oxidative defence genes. These increased ROS levels would set in motion a detrimental cycle of genotoxic damage with rapid erosion and damage of G-rich telomeres, sustained p53 activation, further repression of PGC, progressive mitochondrial decline, and so on37,38
. Under such circumstances, pharmacological correction of increased ROS would not be expected to substantially correct the primary mitochondrial defect and associated degenerative phenotypes, although such interventions may slow the rate of decline. Finally, beyond ROS accumulation, yeast genetic studies have shown that mitochondrial dysfunction results in a decline in iron-sulphur cluster biogenesis39
which can cause nuclear genomic instability and thus would be expected to drive further decline in mitochondrial function via genotoxic activation of p53 and associated repression of PGC. It is also worth noting that p53-mediated repression of PGC is highly context dependent—shown here to occur in the setting of telomere dysfunction with increased p53 levels and activity—and that p53 can exert varied effects on mitochondrial biogenesis and function in other tissue and physiological settings depending on levels and kinetics of p53 activation, among other factors30,40
Mitochondria use oxidative phosphorylation to convert dietary intake into ATP, and in the process, generate ROS which can damage mitochondrial DNA, impair respiratory chain function, and cause nuclear DNA damage and cellular checkpoint activation. Given the central importance of mitochondria, one might anticipate that any genetic manipulation resulting in significantly decreased mitochondrial biogenesis/activity could accelerate the ageing process and cause age-related disorders such as diabetes, heart disease and neurological decline. From this perspective, it is worth noting that there are many molecules with important roles in organismal ageing or age-related disorders which interact directly with components of the telomere-mitochondrial axis. In particular, the increased lifespan associated with caloric restriction in model organisms is accompanied by increased mitochondrial density and respiration. Caloric restriction is associated with increased SIRT1 activity, which stabilizes PGC-1α in turn increasing mitochondrial biogenesis and function41
. Moreover, the beneficial impact of SIRT1 may also stem from its deacetylation and inactivation of p53, which may attenuate checkpoint responses and de-repress PGC-1α expression; conversely, SIRT1 knockout mice show widespread p53 activation and shortened life expectancy42,43
In summary, multiple levels of evidence establish telomere dysfunction-induced p53 represses PGC-1α and PGC-1β, thereby linking telomeres to mitochondrial biology, oxidative defence, and metabolism. As illustrated in , this telomere–p53–PGC pathway expands our understanding of how telomere dysfunction may compromise organ function and contribute to age-related disorders.