The practice of calorie restriction slows all aspects of aging, and produces sweeping changes in the operation of cellular metabolism. This makes for a great deal of work in order to understand how and why it generates beneficial effects. Even separating out root causes from downstream consequences is a slow and expensive challenge for the research community, as understanding calorie restriction must proceed hand in hand with understanding the fine details of cellular biochemistry as a whole - an enormous project that is nowhere near complete. You might look back at the past decade of work on sirtuins for an example of one small slice of the bigger picture, still not complete, and so far undertaken at a cost of hundreds of millions of dollars. In the open access paper noted here, the focus is on one small part of the slowing of immune decline with aging as a result of calorie restriction. As is often the case, the research generates more questions than answers:
In mice, calorie restriction enhances responses to vaccination, reduces the incidence of spontaneous malignancies, and, in some inbred strains, extends lifespan. Specifically, restriction of the calorie intake of C57BL/6J mice by 40% compared to that of mice fed ad libitum (AL), extends median lifespan by more than 35% (i.e., from around 24 months to around 32 months) whereas the lifespan of DBA/2J mice is not extended by calorie restriction. This differential response to calorie restriction may be linked to lower basal metabolic rate, lower oxygen consumption, higher oxidative stress, higher body fat, and continued weight gain throughout adult life in C57BL/6 mice compared to DBA/2 mice fed ad libitum (AL) although differential effects on nutrient sensing cannot be ruled out.
Importantly, age-associated changes in the adaptive immune system - typified by thymic involution, reduced production of naïve T cells, reduced T cell proliferation, reduced cytotoxic T lymphocyte activity, and progressive skewing of the T cell pool toward more mature, memory phenotypes with increasing age - are attenuated by calorie restriction. In mice and in non-human primates, calorie restriction conserves T cell function and repertoire and promotes production and/or maintenance of naïve T cells. The effects of aging and calorie restriction on the innate immune system are, however, much less well studied. Altered function of innate cell lineages of aged individuals has been linked to defective immune regulation and chronic inflammation. In particular, age-associated dysfunction of natural killer (NK) cells has been reported in mice and humans. Progressive narrowing of the NK cell functional repertoire with increasing age may contribute to immune senescence.
NK cells in aged mice appear functionally impaired. Calorie restriction seems to mimic the effects of aging on murine NK cells, with 40% calorie restriction leading to reduced numbers of peripheral NK cells and decreased proportions of the most differentiated NK cell subset in 6-month-old C57BL/6 mice. One study also suggested that CR mice are more susceptible to infection, with lower NK cell activity, again mimicking the effects of aging, although the causal relationship between NK cell function and outcome of infection remains to be tested. Despite evidence that calorie-restriction appears to mimic the effects of aging in murine NK cells, calorie restriction enhances healthy life span in C57BL/6 mice suggesting that age-related changes in murine NK cells may have evolved to preserve innate immune function, and thus resilience in the face of infection, in adult life and thus that there is an underlying unappreciated interaction between age and calorie intake. In an attempt to reveal this interaction, we have - for the first time - analyzed the effects of calorie restriction on NK cell and T cell phenotype and function throughout the life course in C57BL/6J and DBA/2J mice.
To our surprise, the effect of calorie restriction on the NK cell population was to exaggerate, rather than attenuate, the normal age-associated changes in NK cell phenotype and function. Our data suggest that calorie restriction attenuates age-associated effects in T cells but, conversely, accelerates the effects of aging in NK cells, and that the effect of calorie restriction is much more marked in C57BL/6 mice than in DBA/2 mice. The conventional wisdom is that aging is associated with the accumulation of mature, terminally differentiated immune cells with restricted functional capacity, leading to loss of immune integrity, while calorie restriction is believed to preserve immune function, possibly by maintaining the pool of immune cell precursors or stem cells. However, very few studies have looked at the effect of aging or calorie restriction on NK cell function. Overall, calorie restriction had at least as big an effect as age on NK cell and T cell phenotype, and, where aging per se affected immune cells, these effects could be almost totally reversed (in the case of T cells) or were markedly exaggerated (in the case of NK cells) by calorie restriction. The very different effects of age and calorie restriction on T cell and NK cell differentiation and maturation suggest that, despite their many shared features, the underlying response of T cells and NK cells to increasing age and nutritional constraints is, mechanistically, very different.
Similarly, although the immunological effects of aging are very similar in C57BL/6 and DBA/2 mice, the effect of calorie restriction is much less obvious in DBA/2 mice than in C57BL/6 mice. This suggests, but does not prove, that the lack of benefit (in terms of longevity) from calorie restriction in DBA/2 mice may be associated in some way with the failure of the immune system to respond to the change in diet. As discussed above, an intriguing finding from this study is that calorie restriction potentiates age-associated changes in NK cell phenotype and function while simultaneously ameliorating age-associated changes in T cells. However, given the different age-related trajectories of T cell and NK cell populations in control animals, the overall effect of calorie restriction is to maintain larger populations of immature or less differentiated T cells and NK cells. Among NK cells, the maintenance of a less mature phenotype is reflected functionally with increased proliferative responses to cytokine stimulation. This is in partial agreement with evidence from mice and humans, which indicates that less differentiated NK cells express high levels of cytokine receptors and respond strongly to cytokine-mediated signals.
Overall, the effect of calorie restriction is that 22-month-old CR mice retain the immune cell phenotype of 6-month-old conventionally reared mice - the underlying basis for this is not entirely clear. Retention of an immature T cell and NK cell phenotypes in aged, CR mice may result from continuing production of new, immature cells; from accelerated turnover and apoptosis of mature cells; from extension of the life span of individual cells such that they take much longer to mature; or from a combination of any or all of these processes. Our data suggest that calorie restriction may preserve immune function in later life but this is only likely to be beneficial if improved immune function can be achieved whilst still maintaining the energy reserves required to fight infection. More research is required to better understand the interaction between nutritional status, immune function, and healthy aging, in relevant animal models and in humans.