A new study published in Mechanisms of Aging and Development has shown that caloric restriction effectively restores T cell abundance in aged mice [1].
Is it really just about getting fewer calories?
Caloric restriction has become a well-known anti-aging intervention, as it can reverse several hallmarks of aging and extend lifespan in different animal models. Due to the positive effects achieved with caloric restriction and intermittent fasting in animals, many people already practice variations of these regimens. However, the two are distinctly different.
Caloric restriction is simply a reduction of overall calorie intake, while intermittent fasting is a general term for various time-restricted eating regimens that may not necessarily reduce calories. It is still unclear which, if any, of the two is more beneficial for extending human lifespan, particularly in non-obese people who already follow healthy diets. Moreover, there is often overlap between the two in both controlled settings and real situations: time-restricted eating leads to reduced calorie intake and vice versa.
14% caloric restriction was shown to be beneficial even for non-obese healthy people between 24 and 60 years old in the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) trials [2]. However, quality matters as much, if not more, than quantity in diet, and it was shown that the caloric restriction participants followed a nutritionally superior diet according to the diet quality index [3]. This could have contributed to the positive outcomes.
Caloric restriction and the immune system
Participants in one caloric restriction experiment had a greater mass and volume of the thymus, an organ where immune T cell production and maturation takes place [4]. Thymic involution is important in age-associated immune function decline, and efforts are being made to restore this organ in order to achieve some measure of rejuvenation. It would be excellent if simply restricting calories could boost the immune system in this way and ward off infections.
In addition, it was previously shown that caloric restriction attenuates immunosenescence in aged mice [5]. However, the exact mechanisms underlying this phenomenon are still unclear. In this study, the researchers sought to explore the regulation of immunosenescence in mice following caloric restriction in the short and long term.
The diets
Male mice were divided into four groups: a young group on a freely fed normal diet up to the age of 2 months, a control group on a freely fed normal diet up to the age of 6 months followed by a controlled diet (4.5 grams/day) for 12 months, a long-term caloric restriction group on a freely fed normal diet up to the age of 6 months followed by a calorically restricted diet (3.15 g/day), and a short-term caloric restriction group on a freely fed normal diet up to the age of 6 months followed by 11 months on a controlled diet and 1 month on caloric restriction.
Therefore, the experimental groups received 30% fewer calories compared to controls, either over long or short periods of time. Importantly, the control and restricted diets included the same amounts of fiber, vitamins, minerals, and protein. The first change that the researchers observed was an overall weight and fat mass reduction in both short- and long-term calorically restricted groups compared to controls.
The T cells
The cell composition of the spleen was analyzed. Compared to the young group, mice in the control (aged) group were characterized by a decreased number of CD4+ and CD8+ T cells, NK cells, and NKT cells. Long-term caloric restriction reversed these changes except for NK cells. The control group also demonstrated an increase in B cell proportion, but neither of the caloric restriction regimens changed that.
To get a deeper understanding of caloric restriction’s effects on various T cells, the researchers analyzed naive, effector, and memory T cells (both CD4+ and CD8+). The names of these cell types reflect their functions: naive T cells don’t recognize specific antigens and can therefore respond to novel pathogens, effector T cells can interact with specific antigens and give rise to memory T cells, and memory T cells recognize specific antigens from previous encounters.
The researchers show that aging leads to a reduction of naive cells and an increase of effector and memory T cells. Long-term caloric restriction reversed all these changes, while the short-term version only increased the proportion of naive CD8+ T cells.
A closer analysis of effector T cells revealed age-associated changes consistent with increased inflammation in the control group. Long-term caloric restriction somewhat improved the situation but did not reverse the changes completely.
Finally, the researchers assessed if caloric restriction would affect T cell exhaustion, which increases with age. The expression of exhaustion markers was measured, and reduced exhaustion was confirmed in both the short- and long-term groups.
The scientists also measured the expression of the specific transcription factors (TFs) NR4A1 and TOX, which control the exhaustion marker expression. As expected, the expression of these TFs was higher in the control compared to the young group. Long-term caloric restriction brought down the levels of both TFs, whereas the short-term variety reduced only NR4A1.
Abstract
Aging is associated with a decrease in the function of the immune system, a phenomenon known as immunosenescence, which results in reduced resistance to infection. Caloric restriction (CR) is known to prolong lifespan and to regulate immune function. However, whether and how CR affects immunosenescence remains unclear. Here, we evaluated the effect of long- and short-term CR on immunosenescence by subjecting wild-type mice to CR between 6 and 18 months of age or between 17 and 18 months of age, respectively. Compared with a normal diet or short-term CR, long-term CR induced marked or complete attenuation of age-related decreases in the frequency of spleen NK cells and NKT cells; naïve CD4+ and CD8+ T cells; and cytokine- and granzyme B-secreting T cells. In contrast, both long- and short-term CR significantly suppressed age-related upregulation of the T cell exhaustion markers PD-1, Tim-3, and KLRG1, as well as the transcription factors NR4A1 and TOX, which regulate the expression of genes associated with the T cell exhaustion phenotype. These results suggest that CR might suppress age-associated immunosenescence by regulating the expression of transcription factors and target genes that control T cell exhaustion.
Conclusion
The immune system is very complex as evidenced by the plethora of cell types and names used to identify them. It requires fine tuning in order to be efficient at fighting off pathogens while not burdening the organism with excessive inflammation. As demonstrated by this study, both short- and long-term caloric restriction might be a promising approach to attenuate age-accompanied T cell immunosenescence by suppressing cell exhaustion. Although it’s not clear if these results are transferable to humans, the study gives insights about the molecular mechanisms of caloric restriction and some differences between short- and long-term regimens.
Literature
[1] Asami, T. et al. Long-term caloric restriction ameliorates T cell immunosenescence in mice. Mech. Ageing Dev. 206, 111710 (2022).
[2] Dorling, J. L. et al. Effects of caloric restriction on human physiological, psychological, and behavioral outcomes: highlights from CALERIE phase 2. Nutr. Rev. 79, 98–113 (2021).
[3] Racette, S. B. et al. Nutritional quality of calorie restricted diets in the CALERIETM 1 trial. Exp. Gerontol. 165, 111840 (2022).
[4] Spadaro, O. et al. Caloric restriction in humans reveals immunometabolic regulators of health span. Science 375, 671–677 (2022).
[5] Yan, X., Imano, N., Tamaki, K., Sano, M. & Shinmura, K. The effect of caloric restriction on the increase in senescence-associated T cells and metabolic disorders in aged mice. PLoS One 16, e0252547 (2021).
