Control Exercise Calorie Restriction Maximum Life Span Vitetta and Anton 100 ) % ( l a v i v r u S 0 Calorie Restriction Median Life Span (50%) Maximum Life Span young Age old Figure 2 Effect of CR and Exercise on Survival in rats. Adapted and modiﬁed from Holloszy 1995. suggests that sirtuins are involved in promoting longevity, particularly longevity associated with CR regimens, in several organisms. The sirtuin – CR relationship remains complex however. Recently Suave and colleagues (Sauve et al 2006) hypothesized that mammalian SIRT1 may mediate signiﬁcant changes in tissues and endocrine systems through the sensing of low CR diets and triggering physiological changes that beneﬁt mammals with health and hence longevity. Plant factors such as resveratrol have been shown to increase longevity in several organisms by regulating Sir2/SIRT1 (cf. for review: Baur and Sinclair 2006). In mammals, there is growing evidence that resveratrol can prevent or delay the onset of can- cer, heart disease, ischaemic and chemically induced injuries, diabetes, pathological inﬂammation and viral infection. These effects are observed despite extremely low bioavailability and rapid clearance of resveratrol from the circulation (Baur and Sinclair 2006). Resveratrol has been suggested to be associ- ated with the prevention of age-related diseases such as cancer because of its regulation of transcription factors that control tumuor cell survival (Guarente and Kenyon 2000; Howitz et al 2003; Nemoto et al 2005; Storz 2005). Mitochondria and free radicals That mitochondria have a pivotal role in the effective provi- sion of energy to eukaryotic cells is an undisputed scientiﬁc 540 fact. Cellular mechanisms regulating energy utilization must function properly to sustain life. Adenosine 5′–triphosphate (ATP) is the ubiquitous energy storage molecule produced in several cellular processes. Aerobic energy metabolism requires a cellular investment, namely, molecular oxygen. Humans rely on mitochondria to synthesize and export ATP. The process is initiated by the transfer of electrons derived from food sources along a series of mitochondrial respiratory–chain carriers until they are consumed with the production of water from the utilization of oxygen. A single eukaryotic cell may contain between several hundred to thousands of these energy organelles. With increased aging, there is a decrease in mitochondrial energy output (Singh 2006). Hence in aerobic animals, mitochondrial health for effective energy provision is central to life. The free radical theory of aging, as formulated by Denham Harman (1956), is supported by observations that the life span of most organisms is roughly proportional to their metabolic rate and thus due to the rate at which the organism generates mitochondria derived reactive oxygen species (ROS). This view however, is over simplistic and may require modiﬁcation within the conﬁnes of aging. Cellular generated ROS contributing to the overall produc- tion of ROS are apparently traced back to the mitochondria (Lenaz et al 2002). ROS have been viewed as mostly Clinical Interventions in Aging 2007:2(4)