Mitochondria in the signaling pathways that control longevity and health span

Abstract

Genetic and pharmacological intervention studies have identified evolutionarily conserved and functionally interconnected networks of cellular energy homeostasis, nutrient-sensing, and genome damage response signaling pathways, as prominent regulators of longevity and health span in various species. Mitochondria are the primary sites of ATP production and are key players in several other important cellular processes. Mitochondrial dysfunction diminishes tissue and organ functional performance and is a commonly considered feature of the aging process. Here we review the evidence that through reciprocal and multilevel functional interactions, mitochondria are implicated in the lifespan modulation function of these pathways, which altogether constitute a highly dynamic and complex system that controls the aging process. An important characteristic of these pathways is their extensive crosstalk and apparent malleability to modification by non-invasive pharmacological, dietary, and lifestyle interventions, with promising effects on lifespan and health span in animal models and potentially also in humans.

Keywords: Aging; DNA repair; Energy; Lifespan; Metabolism; Mitochondria.

Fig. 1.

Mitochondrial homeostasis and signaling pathways that regulate longevity and health span. Signaling pathways that are activated by insulin and insulin-like growth factor 1 receptors (IR/IGF-1R) includes PI3K-Akt and Ras-Raf-ERK-MAPK pathways leading to the retention of FOXO in cytoplasm, cell growth and proliferation (1), and stimulation of mTOR, and inhibition of autophagy/mitophagy (2). Inhibition of IR/IGF-1R stimulates pathways that regulate mitochondrial maintenance and leads to the translocation of FOXO into the nucleus where it controls the expression of a number of genes including those involved in stress response and immunity (3). Rapamycin (4) and activated AMPK, following increased AMP/ATP ratio (5), inhibit mTOR and stimulate mitochondrial maintenance. NAD⁺ over-consumption following DNA damage, and increased PARylation, reduces SIRT1 activity and mitochondrial biogenesis and maintenance (6). Damage to telomeres may impair mitochondrial biogenesis through activation of p53 and reduced PGC1-a activity (7).

Fig. 2.

NAD⁺ over-consumption following persistent DNA lesions is a central link between nuclear DNA instability and mitochondrial dysfunction, two hallmarks of aging. Defects in DNA repair proteins such as in the premature aging disorders xeroderma pigmentosum group A (XPA), ataxia telangiectasia mutated (ATM), and Cockayne syndrome A and B (CSA/B), as well as age-related DNA repair imbalance and dysregulation (Aging), result in the accumulation of DNA damage and genome instability (1), leading to prolonged PARP activation (PARylation), increased NAD⁺ consumption, and reduced NAD⁺ levels and SIRT 1 activity (2). A consequence of this chain of events is impaired mitochondrial homeostasis, e.g, because of reduced autophagic turnover of mitochondria by mitophagy and mitochondrial biogenesis (3), that in DNA repair deficient disorders contribute to premature aging phenotypes, and in normal aging process leads to diminished tissue and organ function and disease (4).

Fig. 3.

Multiple processes may link nuclear DNA instability to mitochondrial dysfunction and aging, several of which are malleable to modification by lifestyle and drug interventions. Persistent DNA damage and DNA damage response (PARylation), reduces cellular NAD⁺ content resulting in aberrant activity of sirtuins and their downstream targets (1). These events can affect mitochondrial proteins (2) and cytosolic proteins that control mitochondrial quality and mtDNA maintenance (3), leading to mitochondrial stress and loss of mitochondrial homeostasis (4), which ultimately result in tissue and organismal dysfunction (5). Life style and pharmacological interventions (6) may improve health span and increase lifespan by correcting these events (7).