Immune senescence, or a reduction in immune responses, occurs along with many other organ system declines observed in human aging. Immune senescence is characterized by a reduction of naïve T and B lymphocytes and an increase in T and B memory cells. This population shift of lymphocytes causes a reduced response to infection and vaccination as well as an increase in inflammatory cytokines that can contribute to many age-related diseases.

Calorie restriction (CR) diets have been shown to increase the health and lifespan of many model animals. Specifically, in short lived rodent models, these beneficial effects have improved immune system function by enhancing immune competence, inhibiting age-related dysregulation of cytokine secretion, and by preventing the accumulation of senescent T cells through increasing apoptosis.

In a paper previously published by Messaoudi et al. the researchers found that CR diets in long-lived Rhesus monkeys (RM) increased the number and function of naïve and memory T-cells, thus delaying the immune senescence seen in aging immune systems and reproducing the results seen in short-lived model organisms.

In their most recently published study, Messaoudi et al. analyzed the effect of the age-of-onset of CR diets on T-cell homeostasis and function in RM to ascertain the importance of timing the initiation of CR diets throughout the lifespan of RM. In this study, RM began a CR diet as juveniles or in advanced age. In both cases, a CR diet started before or after adulthood negatively impacted immune function.

Optimal window of caloric restriction onset limits its beneficial impact on T-cell senescence in primates. We have recently shown in non-human primates that caloric restriction (CR) initiated during adulthood can delay T-cell aging and preserve naïve CD8 and CD4 T cells into advanced age. An important question is whether CR can be initiated at any time in life, and whether age at the time of onset would modulate the beneficial effects of CR. In the current study, we evaluated the impact of CR started before puberty or during advanced age on T-cell senescence and compared it to the effects of CR started in early adulthood. Our data demonstrate that the beneficial effects of adult-onset CR on T-cell aging were lost by both early and late CR onset. In fact, some of our results suggest that inappropriate initiation of CR may be harmful to the maintenance of T-cell function. This suggests that there may be an optimal window during adulthood where CR can delay immune senescence and improve correlates of immunity in primates.

The peripheral blood of the juvenile CR cohort had the same number of circulating lymphocytes but there was a significant decrease in naïve T cells, and a significant increase in memory T-cells. Additionally, the researchers noted in addition to the decrease in T-cell diversity, an increase in T-cells secreting pro-inflammatory cytokines, and a loss of proliferative potential of T-cells suggesting that early onset of CR diets negatively impacts T-cell aging in male RM.

These phenotypes were not seen in the female juvenile CR cohort. The authors state that this could be due to the fact that the females were 5 years younger on average than the males at the time of peripheral blood sampling. Alternatively, the authors suggest that there may be sex specific effects of CR diets in these animals. But since they did not observe any sex specific differences in their previous study of adolescent CR, the authors conclude that it is more likely that sex differences observed are due to the age discrepancy at the time of the data collection. It will be informative to assess these females in another 5 years to determine if their phenotype mimics the phenotype observed in the males presented here.

In the old age CR cohort, there was no decrease in the population diversity in the circulating T-cells and no difference in numbers of T-cells secreting pro-inflammatory cytokines. However there was an overall reduction in white blood cells, specifically neutrophils, but it is unclear if this phenotype has a detrimental or beneficial effect. Old age CR also resulted in a decreased proliferation potential in T-cells indicating a negative impact of advanced age CR on RM.

This study highlights that appropriate timing of calorie restriction diet onset is critical to observing the beneficial effects on immune senescence. These data also reveal the importance of proper caloric intake during development for healthy immune function. As we improve our understanding of the specific molecular mechanisms by which CR improves health and lifespan we will be better able to treat age-related diseases. Additionally, these non-human primate studies will be exciting to follow as they may prove to be the most relevant animal model to enhance our understanding of molecular mechanisms behind CR diets in humans.