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      The cumulative physiological toll of AL is consistently associated with increasing age in populations worldwide but is nevertheless even detectable in disadvantaged children and adolescents (table 1). From a developmental perspective, we observe that increased AL and senescence interact with a vast array of risk factors and protective factors that carry different health benefits or detriments that affect different age groups in particular. Specifically, such factors as social support, work/home balance, hostility, caregiving, and spirituality are gender typical and of clinical importance as they are steadily associated with increased AL.

      Gender Differences

Gender refers to the implicit and explicit dissimilarities in an array of socioculturally constructed roles, identities, and personality traits that generally predominate in one sex or the other [10]. In general, women self-report more environmental stressors and psychosocial distress, while men are generally more biologically stress responsive compared to women in the follicular phase of their menstrual cycle or on oral contraceptives. These sex differences stem from lifelong exposure to sex steroids in addition to differential patterns of socioculturally constructed gender factors linked to diverse patterns of threat processing and coping mechanisms. Indeed, women demonstrate increased cortisol levels when facing social rejection challenges [15], whereas men tend to be much more reactive when confronted with achievement-based stressors [3] in laboratory paradigms. Therefore, differences in circulating gonadal hormone levels modulate physiological reactivity to stress, but so do elusive gender factors rooted in ethological pressures.

      Evolution of Sex and Gender Differences in Stress

A complementary evolutionary hypothesis put forth by Taylor et al. [16] states that men and women generally cope differently with stress. Accordingly, the primary stress response pattern for men is the ‘fight-or-flight’ response, whereas women might be more prone to engage in ‘tend-and-befriend’ mechanisms, such as nurturing and socializing behaviors that protect against the demands of pregnancy, nursing, and child care. This construct might shed some light on the sex differences found in the AL literature that are moderated by social networks and relational factors (table 1). Furthermore, these gender factors differ significantly from one society and culture to another. In the interest of improving the health and well-being of all citizens, it is important that medical professionals be aware of these subtle yet pronounced nuances between as well as within groups of people. Encouragingly, the AL model has received cross-cultural support, suggesting that it is a promising heuristic platform to explore age, sex, and gender differences vis-a-vis diagnostic criteria, clinical approaches, and perhaps even eventual treatment strategies.

      Treatment

There are currently no published treatment options aimed at lowering AL levels. Nevertheless, many therapeutic options could be implemented based on the vast array of antecedents associated with AL and its clinical repercussions. In the only analyses of unaccountable changes in AL levels in the MacArthur cohort over the span of 2-5 years, Karlamangla et al. [17] showed that deceases in AL were significantly related to reductions in all-cause mortality regardless of one’s sex.

Importantly, there are critical periods to identify and prevent individuals from developing further AL and subsequent disordered, diseased, and deceased endpoints. Population-based analysis using the National Health and Nutrition Examination Survey (NHANES), with over 22,000 participants, has shown that AL steadily increases with age up through the 20s to 60s and then plateaus throughout the 60s to 90s during the period of greatest mortality risk [18].

From the perspectives of the life cycle and AL, this situation suggests decade-long windows of opportunity to intervene before individuals succumb to disease and death. In another NHANES analysis using approximately 15,000 middle-aged and older adults, age attenuated the effects of poverty over time; however, those with high AL had life expectancies 6 years shorter than those at low biological risk with similar poverty status and matched for sex [19]. AL is therefore clinically meaningful.

      Fostering Resilience

The next step for the AL model would be to examine the efficacy of interventions aimed at reducing AL [8]. As outlined by McEwen [20], a key question that arises is whether these interventions should be best tailored in accordance with top-down modifications versus conventional biomedical remediation. At an individual level, brain-centered programs that encourage improved sleep quality/quantity, social support, a sense of purpose, self-esteem, a healthy diet, substance avoidance, and physical activity would be undoubtedly beneficial. Interventions at social levels might include policies that create incentives for beneficial practices in the workplace, cleaner and safer neighborhoods, and motivating higher education.

      Specifically for the elderly, well-being therapy that emphasizes autonomy, purpose in life, personal growth, positive relations with others, environmental mastery, social activities, and self-acceptance could be coupled with more traditional cognitive and physical interventions [8]. These person-centered approaches to diminish AL collectively represent viable alternatives or complements to pharmaceutical strategies, although these must also be considered amid conceptual reluctance.

      Pharmacotherapy

      The effects of chronic stress can be reduced via pharmaceutical agents such as sleep medications, anxiolytics, antidepressants, and β-blockers as well as by drugs that reduce oxidative stress and inflammation such as statins, insulin resistance treatments, and analgesics [20]. However, there are counterarguments against pharmaceutical remediation, especially as they pertain to the widespread systemic dysregulations inherent in AL. In the original formulation of the allostasis concept, Sterling and Eyer [5] argued that medical practices based on homeostatic models were in danger of iatrogenesis (ailments brought forth by a healer) and polypharmacy as treatment problems can arise when correcting one parameter causes dysregulation among other systems. Ultimately, the challenge is to develop pharmaceutical treatments with minimal side effects and inadvertent recalibrations of subsidiary systems. Because AL represents multisystemic, subclinical dysregulations predating the emergence of clinical outcomes, treatment options targeting the aforementioned psychological, behavioral, cognitive, and social domains could be complimentary and indeed facilitative towards improving efficacy and compliance to low-dose pharmacotherapy aimed at proactive prevention instead of reactive prescription.

      Future Directions

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