PGC-1α in aging and anti-aging interventions

doi:10.1016/j.bbagen.2009.04.005

Biochimica et Biophysica Acta (BBA) - General Subjects

Volume 1790, Issue 10, October 2009, Pages 1059-1066

https://doi.org/10.1016/j.bbagen.2009.04.005 Get rights and content

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-1α is a critical regulator of mitochondrial energy metabolism and biogenesis. PGC-1α 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-1α regulation and illustrate how these pathways may be involved in the aging process.

Section snippets

Metabolism and aging

There has been widespread public interest in aging research with particular attention given to aging-associated diseases and the factors that may contribute to disease onset. The fact that aging itself is the most significant risk factor for a range of diseases including, cancer, cardiovascular disease and diabetes [1], emphasizes the need for research on the biology of aging to better understand the underlying causes of aging-associated disease. The advent of transcriptional profiling has

Mitochondrial regulator PGC-1α

PGC-1α is a key regulator of mitochondrial biogenesis and respiration [27], that plays a critical role in the control of metabolism and energy homeostasis [28], [29], [30]. As the transcriptional co-activation of nuclear receptors involved in multiple aspects of metabolism, PGC-1α may play a pivotal role in organismal metabolic homeostasis [31]. PGC-1α is regulated at the protein level by alterations in cellular localization [32], protein stability [32], [33], [34] and post-translational

Post translational modification of PGC-1α

PGC-1α localization, interaction with binding partners and transcriptional co-activation can be manipulated alone or in combination through protein modification. The multiplicity of regulatory points provides enormous versatility and a means to rapidly alter PGC-1α activity in response to a given stimulus. We focus on PGC-1α regulatory factors that have previously been associated with aging or CR and have been designated putative longevity factors in rodent and non-mammalian studies (Fig. 3).

Regulation of PGC-1α activity

Increasing evidence suggests that modifications can result in distinct effects on PGC-1α activity in a manner that is a) stimulus dependent and b) tissue dependent. For example, the mitogen activated kinase p38 has been reported to increase PGC-1α activity upon stress in cardiac myocytes [74], in response to cytokines in myotubes [34] and is required for activation of PGC-1α through calcium calmodulin signaling pathway [75] or in response to trophic factors at the neuromuscular junction [76].

Tissue specific aging and the influence of PGC-1α

The effect of age is often most overt in post-mitotic tissues. Although few studies have directly measured changes in PGC-1α function and activity with age, there are an abundance studies that provide indirect evidence in support of a role for PGC-1α in aging and in anti-aging.

Pharmacological anti-aging strategies: resveratrol

Targeting PGC-1α activity may be a fruitful approach to delay the aging process. Differences in tissue specific roles of PGC-1α and the cross-talk between factors that regulate PGC-1α pose a challenge for design of an agent can actually produce the desired effect. One promising candidate is resveratrol, a plant polyphenol commonly found in red wine that extends lifespan in yeast, worms and flies [143], [144]. Resveratrol treatment activates SIRT1, PGC-1α and AMPK [29], [145], [146], [147], [148]

Conclusion

The quest for new and effective means to delay aging and the onset of aging-associated disease has never looked better. Mechanistic insights in the aging process are being gleaned at an overwhelming rate through studies in cells in culture and in short-lived non-mammalian and mammalian species. The impact of mitochondrial dysfunction is pervasive and as described here likely extends to multiple aspects of normal physiology of aging. We propose that PGC-1α is a very good candidate target to

Acknowledgements

This work was supported by grants from NIH/NIA (AG11915), and NIH/NCRR/CTSA (UL1RR025011). Thanks to Dhanu Shanmuganayagam for critical reading of this manuscript.

References (153)

S.K. Park et al.
Lessons learned from gene expression profile studies of aging and caloric restriction
Ageing Res. Rev.
(2005)
R.H. Eckel et al.
The metabolic syndrome
Lancet
(2005)
F. Lago et al.
The emerging role of adipokines as mediators of inflammation and immune responses
Cytokine Growth Factor Rev.
(2007)
E.J. Masoro
Caloric restriction and aging: an update
Exp. Gerontol.
(2000)
J. Lin et al.
Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor
J. Biol. Chem.
(2002)
J. Lin et al.
PGC-1beta in the regulation of hepatic glucose and energy metabolism
J. Biol. Chem.
(2003)
J. Lin et al.
Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice
Cell
(2004)
Z. Wu et al.
Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1
Cell
(1999)
J.N. Feige et al.
Transcriptional coregulators in the control of energy homeostasis
Trends Cell Biol.
(2007)
M. Sano et al.
Intramolecular control of protein stability, subnuclear compartmentalization, and coactivator function of peroxisome proliferator-activated receptor gamma coactivator 1alpha
J. Biol. Chem.
(2007)

P. Puigserver et al.

Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1

Mol. Cell

(2001)

M. Ichida et al.

Identification of a specific molecular repressor of the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha)

J. Biol. Chem.

(2002)

J. St-Pierre et al.

Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators

Cell

(2006)

A. Wulf et al.

T3-mediated expression of PGC-1alpha via a far upstream located thyroid hormone response element

Mol. Cell. Endocrinol.

(2008)

C. Liu et al.

Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism

Nature

(2007)

R.M. Reznick et al.

Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis

Cell Metab.

(2007)

D.M. Gwinn et al.

AMPK phosphorylation of raptor mediates a metabolic checkpoint

Mol. Cell

(2008)

S. Wullschleger et al.

TOR signaling in growth and metabolism

Cell

(2006)

S.M. Schieke et al.

The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity

J. Biol. Chem.

(2006)

C. Lerin et al.

GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha

Cell Metab.

(2006)

S. Nemoto et al.

SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}

J. Biol. Chem.

(2005)

V.D. Longo et al.

Sirtuins in aging and age-related disease

Cell

(2006)

K.J. Bitterman et al.

Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1

J. Biol. Chem.

(2002)

L. Guarente

Mitochondria — a nexus for aging, calorie restriction, and Sirtuins?

Cell

(2008)

P.T. Bhaskar et al.

The two TORCs and Akt

Dev. Cell

(2007)

S.A. Cook et al.

Transcriptional effects of chronic Akt activation in the heart

J. Biol. Chem.

(2002)

A. Hahn-Windgassen et al.

Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity

J. Biol. Chem.

(2005)

C. Kenyon

The plasticity of aging: insights from long-lived mutants

Cell

(2005)

P.M. Barger et al.

p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response

J. Biol. Chem.

(2001)

D.C. Wright et al.

Calcium induces increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha and mitochondrial biogenesis by a pathway leading to p38 mitogen-activated protein kinase activation

J. Biol. Chem.

(2007)

S. Crunkhorn et al.

Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation

J. Biol. Chem.

(2007)

J.C. Yoon et al.

Suppression of beta cell energy metabolism and insulin release by PGC-1alpha

Dev. Cell

(2003)

P. Zhang et al.

Free fatty acids increase PGC-1alpha expression in isolated rat islets

FEBS Lett.

(2005)

B.N. Finck et al.

Peroxisome proliferator-activated receptor alpha (PPARalpha) signaling in the gene regulatory control of energy metabolism in the normal and diseased heart

J. Mol. Cell. Cardiol.

(2002)

T.R. Koves et al.

Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency

J. Biol. Chem.

(2005)

J.O. Holloszy

Exercise and food restriction in rats

J. Nutr.

(1992)

T. Wenz et al.

Activation of the PPAR/PGC-1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype

Cell Metab.

(2008)

E.J. Masoro

Physiology of aging

Int. J. Sport Nutr. Exerc. Metab.

(2001)

C.K. Lee et al.

Gene expression profile of aging and its retardation by caloric restriction

Science

(1999)

C.K. Lee et al.

Gene-expression profile of the ageing brain in mice

Nat. Genet.

(2000)

C.K. Lee et al.

Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts

Proc. Natl. Acad. Sci. U. S. A.

(2002)

S.A. McCarroll et al.

Comparing genomic expression patterns across species identifies shared transcriptional profile in aging

Nat. Genet.

(2004)

J.M. Zahn et al.

Transcriptional profiling of aging in human muscle reveals a common aging signature

PLoS Genet.

(2006)

K.R. Short et al.

Decline in skeletal muscle mitochondrial function with aging in humans

Proc. Natl. Acad. Sci. U. S. A.

(2005)

K.F. Petersen et al.

Mitochondrial dysfunction in the elderly: possible role in insulin resistance

Science

(2003)

B.E. Wisse

The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity

J. Am. Soc. Nephrol.

(2004)

L. Guarente

Sirtuins as potential targets for metabolic syndrome

Nature

(2006)

R. Weindruch et al.

Influences of aging and dietary restriction on serum thymosin alpha 1 levels in mice

J. Gerontol.

(1988)

R.M. Anderson et al.

Metabolic reprogramming in dietary restriction

Interdiscip. Top Gerontol.

(2007)

A.E. Civitarese et al.

Calorie restriction increases muscle mitochondrial biogenesis in healthy humans

PLoS Med.

(2007)

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Published by Elsevier B.V.

ReviewPGC-1α in aging and anti-aging interventions

Abstract

Section snippets

Metabolism and aging

Mitochondrial regulator PGC-1α

Post translational modification of PGC-1α

Regulation of PGC-1α activity

Tissue specific aging and the influence of PGC-1α

Pharmacological anti-aging strategies: resveratrol

Conclusion

Acknowledgements

Ageing Res. Rev.

Lancet

Cytokine Growth Factor Rev.

Exp. Gerontol.

J. Biol. Chem.

J. Biol. Chem.

Cell

Cell

Trends Cell Biol.

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.

Cell

Mol. Cell. Endocrinol.

Nature

Cell Metab.

Mol. Cell

Cell

J. Biol. Chem.

Cell Metab.

J. Biol. Chem.

Cell

J. Biol. Chem.

Cell

Dev. Cell

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Dev. Cell

FEBS Lett.

J. Mol. Cell. Cardiol.

J. Biol. Chem.

J. Nutr.

Cell Metab.

Physiology of aging

Int. J. Sport Nutr. Exerc. Metab.

Gene expression profile of aging and its retardation by caloric restriction

Science

Gene-expression profile of the ageing brain in mice

Nat. Genet.

Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts

Proc. Natl. Acad. Sci. U. S. A.

Comparing genomic expression patterns across species identifies shared transcriptional profile in aging

Nat. Genet.

Transcriptional profiling of aging in human muscle reveals a common aging signature

PLoS Genet.

Decline in skeletal muscle mitochondrial function with aging in humans

Proc. Natl. Acad. Sci. U. S. A.

Mitochondrial dysfunction in the elderly: possible role in insulin resistance

Science

The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity

J. Am. Soc. Nephrol.

Sirtuins as potential targets for metabolic syndrome

Nature

Influences of aging and dietary restriction on serum thymosin alpha 1 levels in mice

J. Gerontol.

Metabolic reprogramming in dietary restriction

Interdiscip. Top Gerontol.

Calorie restriction increases muscle mitochondrial biogenesis in healthy humans

PLoS Med.

Review
PGC-1α in aging and anti-aging interventions