Axis of ageing: telomeres, p53 and mitochondria

Abstract

Progressive DNA damage and mitochondrial decline are both considered to be prime instigators of natural ageing. Traditionally, these two pathways have been viewed largely in isolation. However, recent studies have revealed a molecular circuit that directly links DNA damage to compromised mitochondrial biogenesis and function via p53. This axis of ageing may account for both organ decline and disease development associated with advanced age and could illuminate a path for the development of relevant therapeutics.

Figure 1. Proposed causes of ageing

Major cellular pathways are implicated in the ageing process. Increased DNA damage, p53 and p16 activity and mitochondrial dysfunction have been shown to promote functional decline and ageing. By contrast, decreased activity in the mammalian target of rapamycin (mTOR), S6 kinase (S6K) and the insulin and insulin-like growth factor 1 (IGF1) pathways increase lifespan in different organisms.

Figure 2. Telomere–p53–PGC pathway

p53 induced by telomere dysfunction binds to the promoters of PPARγ co-activator 1α (PGC1α) and PGC1β and represses the expression of PGC1A and PGC1B. The repression of both co-activators impairs overall mitochondrial biogenesis and function and leads to defective ATP generation and increased levels of reactive oxygen species (ROS). PGCs are also involved in energy metabolism by regulating different biochemical pathways such as fatty acid oxidation, gluconeogenesis, glucose uptake and oxidation. The compromise in mitochondrial function and other biochemical pathways might equally lead to functional decline in tissue stem cells and post-mitotic tissues and drive ageing. Telomerase reactivation or PGC overexpression can reverse PGC-associated metabolic and mitochondrial changes in mice with established telomere dysfunction. Telomere dysfunction may also lead to compromised mitochondrial function and energy metabolism through other pathways (dashed arrows).

Figure 3. A unified theory of ageing

In this model, increased DNA damage (for example, owing to telomere attrition, impaired DNA repair and increased reactive oxygen species (ROS) levels) activates p53, and increasing levels of p53 ultimately lead to compromised mitochondrial function through the repression of PPARγ co-activator 1α (PGC1α) and PGC1β (which promote mitochondrial biogenesis). This p53-mediated mitochondrial dysfunction triggers a cycle of DNA damage (by affecting the production of ROS, iron–sulphur (Fe–S) clusters and NADH/NAD), which in turn leads to further p53 activation and mitochondrial compromise. This feed-forward loop could also account for the divergent and opposite effects of many players in the ageing process. Under mild stress conditions, several components depicted here (p53, mitochondria and AMP-activated protein kinase (AMPK)) have been shown to preserve cellular function but to promote cellular ageing under more severe stress conditions (see text). The interplay between p53 and other pathways that have been implicated in ageing is also indicated. p53 represses the activity of the insulin and insulin-like growth factor 1 (IGF1) pathway and the mammalian target of rapamycin (mTOR) pathway and activates AMPK. How the altered activity of these pathways modifies mitochondrial function and the ageing process in the setting of increased DNA damage is not clear. Other p53-dependent and p53-independent pathways might cooperate in inducing mitochondrial dysfunction. For example, BMI1 indirectly inhibits p53 activation, and BMI1 loss upregulates p16 expression, which increases p53 activity indirectly (dashed arrow) by interacting with MDM2, the negative regulator of p53 (not shown). BMI1 has also been shown to induce mitochondrial dysfunction (probably indirectly). In addition, loss of sirtuins may contribute to mitochondrial dysfunction, as active sirtuin 1 (SIRT1) decreases p53 activity, and loss of SIRT1 promotes p53 activation and its downstream functions. SIRT1 also activates PGC1α and thereby boosts mitochondrial biogenesis. The consequences of mitochondrial dysfunction are, when mild, functional impairment (for example, decreased ATP generation and β-oxidation) without cell loss. However, under increased stress conditions, mitochondrial dysfunction leads to functional impairment and concomitant loss of parenchymal mass owing to increased apoptosis and senescence.