2 A central question concerning longevity remains: Why do some people live long whereas others die early? Another equally critical question concerns morbidity: Why is aging associated with a greater incidence of almost every categoriz- ed disease—including degenerative, metabolic, and malig- nant disorders? Since disease incidence, mortality, and longe- vity are all associated terms in the same aging equation, a more general question may be posed: What are the pathways that impact individuals’ rate of aging? While it is well understood that both biological and psy- chosocial factors impact the aging process, it is still unclear how psychosocial factors inﬂuence cellular aging and trans- late into aging of the whole organism [4]. Below is a selec- tive review focusing on physiological systems susceptible to constitute critical convergence points, acting as integrators of the interactive forces imposed by both biological and psychosocial factors. Understanding how this physiological integration takes place will improve researchers’ means to develop multilevel interventions that optimize the decline in physical function associated with aging. Physical health and function depends on the coordinated functioning of several organs and physiological systems that allow the organism in dynamic balance to adapt to perpetual environmental challenges. Failure to adapt to challenges (e.g., healing wounds, increasing energy expenditure, and replenishing dying postmitotic cells) may occur in aging. Thus, senescence-induced loss of cell numbers and/or opti- mal functioning can result in suboptimal organ function [14]. For this reason, markers of cellular aging, such as nuclear DNA telomere length, is occasionally used as an indicator of aging. These are the protective caps at the end of chromosomes, whose reduction in length is often used as a reliable and proximal indicator of cellular senescence [15]. 2. Biological Determinants of Aging—A Role for the Mitochondrion? Biological factors inﬂuence the aging process. An important constituent of mammalian cells are mitochondria. These dynamic subcellular organelles contain their own circular DNA, are the principal site of cellular adenosine triphosphate (cellular energy currency) synthesis, regulate cell death through apoptotic signalling, and are the major source of reactive oxygen species (ROS) within the cell [16, 17]. One of the most scrutinized hypothesis in aging research is the mitochondrial theory of aging which stipulates that, over time, mitochondrial DNA accumulates oxidative damage from ROS, which negatively impacts mitochondrial fun- ction, leading to cellular dysfunction, organ failure, and ultimately results in age-related disease [14]. Data support- ing this theory has been obtained from transgenic animals with enhanced protection against mitochondrial oxida- tive damage [18, 19]. These mice, which over-express a mitochondrial-targeted catalase, are resistant to age-related insulin resistance [18] and have slightly increased lifespan [19]. However, existing data render this theory imperfect [20–23] and evidence supporting a direct role of ROS in Journal of Aging Research aging has largely been correlative [24]. Furthermore, exam- ples exist in vertebrates (e.g., naked mole rat [25]) and invertebrates (c. elegans [26, 27]) where the typical negative correlation between ROS production and lifespan is uncou- pled. Although ROS-induced damage has not consistently been causally linked to aging, a general shift in intra- and extracellular redox state towards more oxidized levels occurs in aging cells and in the blood of aged individuals, which could have important implications for redox-sensitive signalling pathways and their inﬂuence on the aging process [28, 29]. In contrast, a general role of mitochondria in the aging process is supported by abounding experimental evidence [30–37]. For example, animals with a deﬁcient proof-reading version of the mitochondrial DNA polymerase gamma (PolG mutator mice), a defect which leads to an abnormally rapid accumulation of mitochondrial DNA mutations, exhibit several characteristics reminiscent of an accelerated aging phenotype (e.g., graying of fur, loss of muscle and brain mass, and kyphosis) [38, 39]. This indicates that mitochon- drial DNA damage is capable of causing aging-like symptoms such as organ dysfunction and early mortality. It must be noted that whether this model actually mimics natural human aging is uncertain [40, 41]. Similarly, whether ROS dictates the aging process [23] remains a contentious issue. Nevertheless, although its exact cellular and physiological impact remain unclear, the integrity of mitochondrial DNA is challenged during aging [42, 43] and may contribute to cellular senescence and consequently, to the progressive fun- ctional changes in organs that characterize the aging process. Further evidence supporting a role of mitochondria in the aging process comes from interventions that inﬂuence mitochondrial function. The only intervention capable of extending life span in animals—lifelong caloric restric- tion [44]—diminishes damage to mitochondrial DNA and concomitantly decreases the age-related decline in muscle aerobic capacity [45, 46]. Of note, caloric restriction has also been reported to decrease the incidence of age-related ill- nesses (e.g., cancer) in rodents [47], providing an interesting empirical link between mitochondrial integrity and age- related morbidity. Moreover, evolutionarily inherited sin- gle nucleotide polymorphisms yielding genetic variants of mitochondrial DNA, called haplogroups, may inﬂuence mitochondrial function and health outcomes in humans (reviewed in [14]). Indeed, mitochondrial haplogroups have been associated with mitochondrial ROS production and cellular oxidative capacity [48–50], resting metabolic rate and energy expenditure in humans [51], and disease inci- dence, progression, and longevity [14, 52–54]. Collectively, this suggests that intrinsic mitochondrial factors (e.g., related to mitochondrial DNA) can indeed inﬂuence the aging process. Like caloric restriction, physical activity and exercise are potent stimuli that increase mitochondrial content and function [55–57]. Physical activity reduces the age-related decline in function of diﬀerent organ systems including brain and muscles. Indeed, it is established that individuals who are more physically active exhibit lower incidences of age-related diseases and mortality [58–60] as well as better control of