Studenski, Stephanie A.

Degeneration of the thymus and severe contraction of the T‐cell repertoire with aging suggest that immune homeostasis in old age could be mediated by distinct effectors. Therefore we examined receptors expressed on T cells as they undergo senescence in vitro , and those displayed by circulating T cells during normal chronologic aging. Monitoring of T cells driven to senescence showed de novo induction of CD56, the prototypic receptor of NK cells. Analysis of fresh T cells in blood showed an age‐dependent induction of CD56. These unusual T cells expressed high levels of Bcl2, p16, and p53, and had limited, or completely lost, ability to undergo cell division; properties consistent with senescence. CD56 cross‐linking without TCR ligation on CD56 + T cells resulted in extensive protein phosphorylation, NFκB activation, and Bax down‐regulation. CD56 cross‐linking was also sufficient to drive production of various humoral factors. These data indicate that the immunologic environment in old age is functionally distinct, rather than a dysfunctional version of that seen at a young age. In view of the reported inefficiencies of TCR‐driven immunity with aging, elicitation of TCR‐independent immune cascades by CD56 + T cells provide new avenues for the development of alternative strategies to enhance protective immunity in the elderly. [Supported by NIH grants R01‐AG022379, R01‐AG023629, P20‐CA103730, and T35‐AG026778].

Abstract Recent study has shown that incident dementia risk is higher among older persons who decline in both cognition and gait. This study assesses whether this relationship exists in multiple other aging populations. Data are from the Baltimore Longitudinal Study of Aging (n=662, 51%women,22%blacks), Health, Aging and Body Composition Study (n=746, 51%women,44%blacks), and Mayo Clinic Study of Aging (n=2771, 48%women,0.3%blacks). Participants were at least 60, initially free of cognitive impairment, dementia, and dismobility (gait speed≤0.6m/s), with repeated measures of verbal memory and gait speed before dementia diagnosis (average follow-up 5.8-12.1 years). Within each cohort, participants were divided into four groups: memory decliners alone, gait decliners alone, dual decliners, or neither (healthy agers). Gait speed decline was defined as a loss of ≥0.05m/sec/year; memory decline was defined as cohort specific bottom slope tertile. Incident dementia risk was examined by Cox regression with healthy agers as reference, adjusted for sex, race, baseline age, gait speed and memory. Across studies, incident dementia ranged from 3% to 17%. Compared to healthy agers, memory decliners alone had 3.4 to 4.3 times higher risk for developing dementia (p<0.01). Gait decliners alone had 2.1-5.6 times higher risk for dementia (p<0.05). Dual decliners had 7.6-10.8 times the risk (p<0.001). Dual decline signifies a more rapid progression to dementia. These consistent findings suggest that dual decliners might be a potentially valuable target group for both preventive interventions and mechanistic studies. Whether dual decline identifies a particular subtype or multiple subtypes of dementia remains to be investigated.

The American Geriatrics Society convened a conference in Bethesda, Maryland, to explore models and studies of aging. This was the second of three conferences, supported by a U13 grant from the National Institute on Aging, to aid recipients of Grants for Early Medical/Surgical Specialists Transition to Aging Research (GEMSSTAR) in integrating geriatrics into their specialties. Recognizing that aging is the largest risk factor for multiple chronic diseases and age‐related loss of resilience, the conference organizers focused scientific sessions on how targeting age‐related mechanisms can delay, prevent, or reverse geriatric syndromes, age‐related chronic diseases, and loss of resilience. The rationale for studying models of aging as well as study designs, strategies, and challenges of studying human aging were reviewed. This article provides a summary of the full conference report, Models and Studies of Aging: Report from the U13 Conference Series, and summarizes key take‐home messages that were designed to support GEMSSTAR awardees in developing their research careers focused on aging research (see supplementary text for the full report). J Am Geriatr Soc 67:428–433, 2019.

Abstract Degeneration of the thymus and severe contraction of the T cell repertoire with aging suggest that immune homeostasis in old age could be mediated by distinct effectors. Therefore, receptors expressed on T cells as they undergo senescence in vitro, as well as those displayed by circulating T cells during normal chronologic aging, were examined. Monitoring of T cells driven to senescence showed de novo induction of CD56, the prototypic receptor of NK cells. Analysis of fresh T cells in peripheral blood showed an age-dependent induction of CD56. These unusual T cells expressed high levels of Bcl2, p16, and p53, and had limited, or completely lost, ability to undergo cell division, properties consistent with senescence. CD56 cross-linking without TCR ligation on CD56+ T cells resulted in extensive protein phosphorylation, NF-κB activation, and Bax down-regulation. CD56 cross-linking was also sufficient to drive production of various humoral factors. These data suggest that the immunologic environment in old age is functionally distinct, rather than being a dysfunctional version of that seen at a young age. CD56+ T cells are unique effectors capable of mediating TCR-independent immune cascades that could be harnessed to enhance protective immunity in the elderly.