Journal of Aging Research existing chronic diseases [60]. Furthermore, endurance exer- cise prevents the premature aging-like characteristics of the PolG mutator mice including mitochondrial abnormalities, skeletal muscle, and brain atrophy [61]. The converse is also true. Physical inactivity leads to a reduction in mitochondrial content and function [56, 62] and contributes towards insulin resistance (i.e., prediabetic state) [63] and enhanced metabolic risk [64]. The aforementioned physiological dysregulations are more commonly observed in old age. For example, older individuals (63–70 years old) who are sedentary, but not those who are active, have lower mitochondrial content than young individuals [65]. Finally, dietary lipid supply (e.g., virgin olive oil) has been shown to impact membrane composition in brain mitochondria and to reduce oxidative damage to these organelles with aging in rats [66]. Thus, factors that impact mitochondrial function (i.e., levels of physical activity, caloric restriction, and diet) can conse- quently impact age-related disease incidence, progression, and survival. The ﬁndings outlined in this section are consistent with the notion that biological mechanisms determine the aging process. Additional arguments supporting this notion also exist. They notably include the loss of molecular ﬁdelity with time as the major cause of aging [67] and the recently discovered link between mitochondrial function, telomere length, and cellular senescence [68, 69]. Because each aspect outlined above appears to modulate the aging process in small yet sizeable ways, we must acknowledge that evidence suggests that the rate of aging is not solely determined by single biological factors, such as how many calories are ingested, which genetic polymorphism an individual has inherited, and how much physical activity is performed. Rather, in real-life situations, the rate of aging for a given individual must ultimately be determined by the dynamic and reciprocal interplay of these and many other factors, as discussed below. 3. Psychosocial Determinants of Aging Despite the fact that aging research has generally been dis- sected using the biological scalpel, psychological and social variables are also important modulators of the aging process associated with mortality [70–73]. For example, personality and lifestyle may inﬂuence longevity in humans [4]. In a prospective study of patients with coronary heart disease, the authors found that pessimism and anxious personality traits were associated with adverse age-related health outcomes such as greater cancer incidence [74] and all-cause mortality [75]. Degradation in negative aﬀect (i.e., more negative emotions) was also a strong prognostic indicator of long- term mortality in coronary heart disease patients [76], suggesting that negative emotions can adversely inﬂuence survival and resilience. On the other hand, centenarians with engaged lifestyle and certain personality traits (e.g., emotional stability, extra- version, and openness) tend to have higher mental health sta- tus, a healthy sign of aging, when compared to those who do 3 not possess these traits [77]. A twenty-year prospective popu- lation study showed that individuals with more positive self- perceptions of aging tended to live about seven years longer than those with less positive perceptions of aging [78]. Like- wise, self-rated health—SRH, how an individual subjectively rates his/her health—is one of the most powerful statistical predictor of morbidity and mortality [79, 80]. Of note, SRH is often a more powerful statistical predictor of mortality than clinical and biological assessments of health. Similarly, high socioeconomic status is associated with more positive multisystemic physiological proﬁles (i.e., allostatic load), which predict lower morbidity and mortality rates with aging [81, 82]. There is also evidence that “protective” psychosocial factors such as control beliefs and quality of social support (i.e., emotional links with family and friends) contribute to better maintenance of functional capacity with aging [83]. Although not directly supporting a causal link between psychosocial factors and longevity, these data strongly sug- gest that several psychosocial factors impact physiological pathways to aging and distal outcomes such as mortality and longevity. Psychosocial factors also have similar eﬀects on more proximal biological indices of aging. Not living with a part- ner (i.e., being unmarried) is associated with accelerated cel- lular aging, as evidenced by shorter telomere length in blood leukocytes of unmarried middle-aged men and women [84]. Similar reports by Epel and colleagues demonstrate that psychological stress is associated with accelerated telomere shortening [85]. Likewise, depression has been linked with accelerated rates of aging and cellular senescence [86] and mortality [75], demonstrating that psychosocial forces may accelerate cellular aging [72]. Collectively, these ﬁndings indicate that psychosocial forces can exert both negative and positive inﬂuences on the aging process, aﬀecting both mor- bidity and mortality. 4. Mitochondria: Interfacing Two Worlds As mentioned above, mitochondria inﬂuence cellular func- tion [16, 17] and impairments in mitochondrial function due to genetic variations/mutations [14] or other stresses such as physical inactivity [56] may accelerate the aging process. Interestingly, several hormones including those involved in the body’ stress responses to psychosocial stressors modulate the synthesis of new mitochondria (mitochondrial biogene- sis) and can modify important parameters of mitochondrial function [87]. Indeed, mitochondrial DNA transcription and mitochondrial biogenesis are modulated by the glucocorti- coid hormone cortisol downstream from the hypothalamic- pituitary-adrenal (HPA) axis, by catecholamines secreted by the sympathetic-innervated adrenal medulla (epinephrine and norepinephrine), thyroid hormones, and by the steroid hormone estrogen, as well as by several cytokines (e.g., IL-1α, IL-1β, and TNFα) [88]. In fact, the mitochondrial DNA sequence contains putative response elements for several hormonal receptors (e.g., thyroid and glucocorticoid hormones, and insulin) [89] and some receptors for glucocorticoids, thyroid hormones,