PGC-1alpha in aging and anti-aging interventions

Abstract

Deregulation of mitochondrial function is a common feature in multiple aspects of aging. In addition to playing a role in aging-associated disease, decline in mitochondrial energy metabolism is likely to be important in the development of metabolic disease. Furthermore, altered mitochondrial function is a conserved feature in caloric restriction--a dietary intervention that delays aging in diverse species. The transcriptional co-activator PGC-1alpha is a critical regulator of mitochondrial energy metabolism and biogenesis. PGC-1alpha is uniquely poised as a potential target for correcting the effects of age on mitochondrial decline. We describe the cellular and tissue specific mechanisms of PGC-1alpha regulation and illustrate how these pathways may be involved in the aging process.

Figure 1. The role of mitochondrial metabolism in aging and disease

The loss of mitochondrial efficiency and energetic capacity is a unifying feature in the onset of morbidities due to dietary, genetic or aging influences. A causal role in the aging process is suggested and enabled through the complex interplay among distinct tissues in response to metabolic defects. In contrast, altered mitochondrial metabolism is a conserved feature of caloric restriction, the most robust intervention that delays aging in numerous species.

Figure 2. Mitochondrial regulation through PGC-1α in response to diverse stimuli

Mitochondrial metabolism can be regulated rapidly through changes in PGC-1α transcriptional activity. The wide range of stimuli that impact PGC-1α speaks to a central role for mitochondrial adaptation in the cellular response. Loss of mitochondrial plasticity and the ability to respond appropriately to changes in the cellular environment may contribute to metabolic derangements associated with the aging process.

Figure 3. PGC-1α is regulated through post-translational modification

These highly simplified illustrations are intended to convey conceptually how the metabolic impact of any given stimulus can be tailored through alterations in PGC-1α localization, binding partners and gene target specificity. A. Mitochondrial adaptation in response to changes in nutrient availability is achieved through a balance of factors that regulate PGC-1α levels and activity. It is likely that PGC-1α function is not equivalent in each response due to simultaneous regulation of PGC-1α binding partners. B. Tissue specificity plays an important role in the response of PGC-1α to the fed or fasted state. The appropriate response to fasting requires increased glucose output from liver and reduced glucose utilization in skeletal muscle, both of which involve PGC-1α. The use of the same regulator in each tissue ensures a coordinated response. C. PGC-1α localization and stability is regulated in response to stress. Transient activation of mitochondrial metabolism is an early event in the stress response. PGC-1α accumulates in the nucleus and is degraded following transcriptional activation. A strategy of altering PGC-1α protein turnover provides a sensitive and rapid mechanism for regulation of mitochondrial metabolism.

Figure 4. Activation of PGC-1α by resveratrol

Increased PGC-1α activity is accomplished through regulation of a combination of factors involved in modulating PGC-1α. The positive effect of resveratrol on SIRT1 and AMPK, activators of PGC-1α, is augmented by the negative effect on AKT inhibitor of PGC-1α. Resveratrol treatment has been shown to improve parameters of aging at low doses in mice (see text) although its impact on aging in primates is not known.