Mutations in mitochondrial DNA (mtDNA) accumulate in tissues of mammalian species and have been hypothesized to contribute to aging. We show that mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g (POLG) accumulate mtDNA mutations and display features of accelerated aging. Accumulation of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cellular turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. Thus, accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging.

Recent scientific studies have advanced the notion of chronic inflammation as a major risk factor underlying aging and age-related diseases. In this review, low-grade, unresolved, molecular inflammation is described as an underlying mechanism of aging and age-related diseases, which may serve as a bridge between normal aging and age-related pathological processes. Accumulated data strongly suggest that continuous (chronic) up-regulation of pro-inflammatory mediators (e.g., TNF-α, IL-1β, 6, COX-2, iNOS) are induced during the aging process due to an age-related redox imbalance that activates many pro-inflammatory signaling pathways, including the NF-κB signaling pathway. These pro-inflammatory molecular events are discussed in relation to their role as basic mechanisms underlying aging and age-related diseases. Further, the anti-inflammatory actions of aging-retarding caloric restriction and exercise are reviewed. Thus, the purpose of this review is to describe the molecular roles of age-related physiological functional declines and the accompanying chronic diseases associated with aging. This new view on the role of molecular inflammation as a mechanism of aging and age-related pathogenesis can provide insights into potential interventions that may affect the aging process and reduce age-related diseases, thereby promoting healthy longevity.

SummaryA decline in mitochondrial function plays a key role in the aging process and increases the incidence of age-related disorders. A deeper understanding of the intricate nature of mitochondrial dynamics, which is described as the balance between mitochondrial fusion and fission, has revealed that functional and structural alterations in mitochondrial morphology are important factors in several key pathologies associated with aging. Indeed, a recent wave of studies has demonstrated the pleiotropic role of fusion and fission proteins in numerous cellular processes, including mitochondrial metabolism, redox signaling, the maintenance of mitochondrial DNA and cell death. Additionally, mitochondrial fusion and fission, together with autophagy, have been proposed to form a quality-maintenance mechanism that facilitates the removal of damaged mitochondria from the cell, a process that is particularly important to forestall aging. Thus, dysfunctional regulation of mitochondrial dynamics might be one of the intrinsic causes of mitochondrial dysfunction, which contributes to oxidative stress and cell death during the aging process. In this Commentary, we discuss recent studies that have converged at a consensus regarding the involvement of mitochondrial dynamics in key cellular processes, and introduce a possible link between abnormal mitochondrial dynamics and aging. Journal of Cell Science (Chen and Chan, 2009). However, the relevance of mitochondrial fusion and fission to underlying mechanisms of aging has not been fully appreciated, in part because the molecular events that underlie the aging process have not yet been completely elucidated. In this Commentary, we discuss current knowledge of mitochondrial dynamics, structure and function in relation to key cellular events, including mitochondrial biogenesis, mtDNA homeostasis, autophagy and cell death. By providing a basic overview of mitochondrial fusion and fission events and their general function in these crucial biological processes during normal stable environmental conditions, we hope to portray how alterations in mitochondrial dynamics can contribute to the mitochondrial dysfunction that is commonly associated with aging. Mechanisms underlying mitochondrial dynamicsMitochondria are highly complex and dynamic organelles that can alter their organization, shape and size, depending on intracellular and extracellular signals (Bereiter-Hahn and Voth, 1994;Rube and van der Bliek, 2004). Mitochondria undergo a continuous cycle of fusion and fission, and the balance between these opposing events determines the morphology of the organelle (Chen and Chan, 2004) (Fig. 2). Whereas decreased fusion can result in mitochondrial fragmentation because of excessive fission, decreased fission can generate long and highly interconnected mitochondria (Sesaki and Jensen, 1999).During the past decade, various cellular components have been identified as key mediators of mitochondrial fusion and fission in yeast (Hoppins et al., 2007;Merz et al., 2007;Okamoto and Shaw, 2005). The...