Journal of Aging Research Biological factors - Genetic and epigenetic modiﬁcations - Physical activity and inactivity levels - Diet - Metabolic balance - Allostatic load, neuro- hormonal mediators - Inﬂammation Psychosocial factors - Self-perceptions of health and aging - Psychosocial stress - Socioeconomic status - Social support - Sense of purpose in life - Personality - Emotions - Psychopathology n o i t c n u f l a i r d n o h c o it Acute M Chronic Duration of stress Mitochondria - mtDNA variants (haplogroups) - mtDNA mutations/ damage - Dynamics (fusion and ﬁssion) ROS Apoptosis ATP synthesis SAM metabolism NAD+ · · · Pathways to aging - Redox status - Epigenetic modiﬁcations - Telomere shortening - · · · - Resiliency - Rate of aging - Comorbidities - Mortality 5 Figure 1: Mitochondria inﬂuence pathways to aging by operating at the intersection of biological and psychosocial factors. Biological and psychosocial factors dynamically/bidirectionally interact to inﬂuence mitochondrial content and function in the body’s tissues. The same factors can exert opposite eﬀects on mitochondrial function, depending on the duration of exposure. For instance, acute stressors tend to upregulate mitochondrial biogenesis and function, whereas chronic stressors tend to downregulate mitochondrial biogenesis and function (top center graph). Mitochondrial-level factors inﬂuence mitochondrial function and may determine mitochondrial responsivity to upstream biological and psychosocial inﬂuences. In response to multiple individual and environmental factors, mitochondria produce outputs inﬂuencing cellular function, gene expression, and cellular senescence. As a result, pathways to aging are ultimately determined by the integrated and synergistic inﬂuence of multiple biological and psychosocial factors. Table 1: Research propositions to advance knowledge of healthy aging—Adapted from Ryﬀ and Singer [70]. Proposition 1 Proposition 2 Proposition 3 Proposition 4 Proposition 5 Health promotion processes: positive psychosocial factors predict better biological regulation Premise: positive health and high levels of well-being are associated with lower morbidity, decreased physical symptoms and pain, increased longevity, increased resistance to illness, decreased stroke incidence, and better glycemic control. Resilience Processes: positive psychosocial factors protect against the damaging eﬀects of external adversity Premise: psychological strengths (e.g., personality traits and coping ability) and favourable social situations (e.g., social/family support and high socioeconomic status) are associated with “physiological toughness” and an enhanced ability to maintain a high-level of functioning in the face of adversity. Recovery and repair processes: Positive psychosocial factors facilitate the regaining of functional and/or biological capacities Premise: hopeful individuals with optimistic beliefs and positive expectations about their health have better prognosis from heart surgeries, some cancers and HIV/AIDS, and possibly better DNA repair mechanisms. Compensation processes: psychological or biological strengths can oﬀset the negative health consequences of psychological or biological weaknesses Premise: psychological distress and adversity can be moderated by positive psychological traits (e.g., coping strategies and aﬀective styles). Gene expression processes: psychosocial factors as mitigating against the negative and promoting the positive Premise: many people with genetic susceptibilities to certain diseases never develop them; psychosocial and other environmentallydriven epigenetic factors may modulate genetic susceptibility to disease and gene expression patterns that impact health in aging.