The novel and significant initial findings of this study include that community-dwelling frail older adults had higher total CCR5+, CCR5+CD8+, and CCR5+CD45RO− T-cell counts than age-, race-, and sex-matched nonfrail controls. With careful control of major demographic variables and comparable clinical profiles between the two study groups, the observed expansion of the CCR5+ T-cell population appears to be specific in frailty, above and beyond age-related T-cell remodeling, although these initial findings will need to be confirmed in large prospective studies.
Aging is associated with significant skewing of the immune repertoire to the memory phenotype.18,19
Consistent with this, it was observed that more than 50% of the total T-cell pool had a CD45RO+
memory phenotype in frail and nonfrail participants. No differences were observed between the two study groups in CD45RO+
memory T-cell counts. In contrast, it was observed that frail older adults had higher CD8+
T-cell counts than matched nonfrail controls. This is consistent with the findings from a recent study that frailty is associated with higher frequencies of CD8+
T-lymphocytes in older women.20
CCR5 is expressed on T-lymphocytes, monocytes, dendritic cells, and macrophages.8,9
Greater CCR5 gene expression in T-cells during aging has been demonstrated in humans and rodents at the messenger ribonucleic acid level and according to Western blotting,21,22
although the functional implication of this finding is unknown. Greater expression of chemokines and chemokine receptors, including CCR5, has been implicated in Alzheimer’s disease and other neurodegenerative diseases in which significant neuroinflammation is present.23,24
Although no significant differences in peripheral lymphocyte or total T-lymphocyte counts were observed between frail and nonfrail participants, the present study found that frail participants had higher percentages and absolute counts of total CCR5+
, and CCR5+
T-cells than matched nonfrail controls, suggesting, for the first time, significant expansion of a specific T-cell subset with a type-1 proinflammatory phenotype in frail older adults. The observed trend of graded increase in the CCR5+
T-cell counts across frailty scores in frail participants (), although preliminary, further suggests that CCR5+
T-cell counts may be correlated with frailty severity. The current evidence suggesting chronic inflammation as a key pathophysiological factor in frailty supports these observations. It may be that CCR5+
T-cells play an important role in the pathogenesis of frailty through their potential contribution to chronic inflammation in older adults, in addition to age-related immune remodeling.
These findings, if validated, have significant clinical and therapeutic implications. Anti-CCR5-based interventional strategies, with monoclonal antibodies or specific antagonists, have been highly successful in the treatment of HIV infection and AIDS in animal models and clinical trials.15,16
It is tempting to speculate that anti-CCR5-based strategies can be developed for the prevention or delay and treatment of the frailty syndrome in older adults.
No definitive conclusions can be drawn from this study because of its cross-sectional design with a small sample size. Nevertheless, these initial findings support the hypothesis and open a new and potentially important research avenue for better understanding of the pathogenesis of frailty. They also provide a basis for further evaluation of the CCR5+ T-cell subpopulation and its role in the development of frailty in older adults.