ne of the most important medical discoveries of the past two decades has been that the immune system and inflammatory processes are involved in not just a few select disorders, but a wide variety of mental and physical health problems that dominate present-day morbidity and mortality worldwide 1-4. Indeed, chronic inflammatory diseases have been recognized as the most significant cause of death in the world today, with more than 50% of all deaths being attributable to inflammation-related diseases such as ischemic heart disease, stroke, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease (NAFLD) and autoimmune and neurodegenerative conditions 5. Evidence is emerging that the risk of developing chronic inflammation can be traced back to early development, and its effects are now known to persist throughout the life span to affect adulthood health and risk of mortality 6-8. In this Perspective, we describe these effects and outline some promising avenues for future research and intervention. Inflammation Inflammation is an evolutionarily conserved process characterized by the activation of immune and non-immune cells that protect the host from bacteria, viruses, toxins and infections by eliminating pathogens and promoting tissue repair and recovery 2,9. Depending on the degree and extent of the inflammatory response, including whether it is systemic or local, metabolic and neuroendocrine changes can occur to conserve metabolic energy and allocate more nutrients to the activated immune system 9-12. Specific biobehavioral effects of inflammation thus include a constellation of energysaving behaviors commonly known as "sickness behaviors, " such as

Highly active antiretroviral treatment has resulted in dramatically increased life expectancy among patients with HIV infection who are now aging while receiving treatment and are at risk of developing chronic diseases associated with advanced age. Similarities between aging and the courses of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome suggest that HIV infection compresses the aging process, perhaps accelerating comorbidities and frailty. In a workshop organized by the Association of Specialty Professors, the Infectious Diseases Society of America, the HIV Medical Association, the National Institute on Aging, and the National Institute on Allergy and Infectious Diseases, researchers in infectious diseases, geriatrics, immunology, and gerontology met to review what is known about HIV infection and aging, to identify research gaps, and to suggest high priority topics for future research. Answers to the questions posed are likely to help prioritize and balance strategies to slow the progression of HIV infection, to address comorbidities and drug toxicity, and to enhance understanding about both HIV infection and aging.

The strict limit in proliferative potential of normal human somatic cells - a process known as replicative senescence - is highly relevant to the immune system, because clonal expansion is fundamental to adaptive immunity. CD8(+) T cells that undergo extensive rounds of antigen-driven proliferation in cell culture invariably reach the end stage of replicative senescence, characterized by irreversible cell-cycle arrest and a critically short telomere length. Cultures of senescent CD8(+) T cells also show resistance to apoptosis, permanent loss of CD28 expression, altered cytokine profiles, reduced ability to respond to stress, and various functional changes. Cells with similar characteristics accumulate during normal aging as well as in younger persons infected with human immunodeficiency virus, suggesting that the process of replicative senescence is not an artifact of cell culture but is also occurring in vivo. Interestingly, in elderly persons, the presence of high proportions of CD8(+) T cells with characteristics of replicative senescence is correlated with reduced antibody responses to vaccines as well as with osteoporotic fractures. CD8(+)CD28(-) T cells also accumulate in patients with certain types of cancer. The emerging picture is that senescent CD8(+) T cells may modulate both immune and non-immune functions, contributing not only to reduced anti-viral immunity but also to diverse age-related pathologies.

HIV risk behaviors, susceptibility to HIV acquisition, progression of disease after infection, and response to anti-retroviral therapy all vary by age. In those living with HIV, current effective treatment has increased the median life expectancy to > 70 years of age. Biologic, medical, individual social and societal issues change as one ages with HIV infection, but there has been only a small amount of research in this field. Therefore, the Office of AIDS Research of the National Institutes of Health commissioned a working group to develop an outline of the current state of knowledge and areas of critical need for research in HIV and Aging; the working groups’ findings and recommendations are summarized in this report. Key overarching themes identified by the group included: multi-morbidity, poly-pharmacy and the need to emphasize maintenance of function; the complexity of assessing HIV vs. treatment effects vs. aging vs. concurrent disease; the inter-related mechanisms of immune senescence, inflammation and hypercoagulability; the utility of multi-variable indices for predicting outcomes; a need to emphasize human studies to account for complexity; and a required focus on issues of community support, caregivers and systems infrastructure. Critical resources are needed to enact this research agenda and include expanded review panel expertise in aging, functional measures and multi-morbidity, as well as facilitated use and continued funding to allow long-term follow-up of cohorts aging with HIV.

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