T Cell Subset Patterns That Predict Resistance to Spontaneous Lymphoma, Mammary Adenocarcinoma, and Fibrosarcoma in Mice

Abstract

Aging leads to changes in the proportion of several T cell subsets in peripheral blood, but it is not yet known whether these changes have prognostic significance for late-life diseases. To examine this question, levels of T cell subsets were measured at 8 and 18 mo of age in the peripheral blood of mice of a genetically heterogeneous stock, and the mice were then subsequently evaluated for life span and for cause of death. The results indicate that mice whose T cell subset patterns look like those of old mice tend to die at earlier ages, regardless of the specific cause of death. At 18 mo, 39% of the variance within the set of seven measured subsets could be combined statistically into a single number, whose correlation with individual subsets suggested that it could be interpreted as an index of immunological aging. T cell subset pattern, as represented by this index, was a predictor of life span in mice dying of lymphoma, fibrosarcoma, mammary adenocarcinoma, or of all other causes considered together. Even as early as 8 mo of age, T cell subset patterns are significant predictors of all three forms of cancer, although at this age the association is stronger in mated female mice than in virgin mice. These results support two controversial hypotheses, which are not mutually exclusive: 1) early immune senescence might predispose to early death from cancer and 2) differences in aging rate, as monitored by tests of immune status, might accelerate or decelerate a wide range of late life neoplastic diseases.

Do thymically and strictly extrathymically developing T cells generate similar immune responses?

“…58 Several observations suggest that immune competence has a major influence on lifespan and that changes in T-lymphocyte populations could be implicated in the age-related increase in incidence of infections, cancer, and autoimmune diseases. 57,59,60 Therefore, strategies to rejuvenate the thymus or to create thymus substitutes are being pursued with intense interest. [61][62][63][64] That OM ϩ extrathymic T cells cannot substitute for thymic T cells even though they have a diversified TCR repertoire implies that having the ability to generate new T cells is not sufficient to ensure immunocompetence.…”

Exploiting the rodent model for studies on the pharmacology of lifespan extension

“…The result was that another mouse simply moved up the hierarchy to become the dominant mouse. Miller & Chrisp (2002) reported an unexpectedly high incidence of mouse urinary syndrome (MUS) in a lifespan study of four-way cross HET mice. It was restricted to males and it appeared that the syndrome resulted from dominance aggression between individuals.…”

Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction

“…Inhibitors of mTOR function can block tumor growth directly (Hidalgo & Rowinsky, 2000), and it is plausible that direct effects on tumors may contribute to lifespan effects in mice, in which tumors are the most frequent class of lethal illness (Miller & Chrisp, 2002; Lipman et al ., 2004). Enteric-released rapamycin-treated UM-HET3 mice, however, show decelerated rates of change in a wide range of age-related physiological and pathological endpoints (Wilkinson et al ., 2012), suggesting that the drug may be inhibiting at least some aspects of the aging process in addition to any direct effects it may have on cancer cells.…”