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Caloric Restriction Attenuates Immunosenescence

Caloric restriction and senolytics seem to have some similar effects.

Time restricted eatingTime restricted eating

Scientists have shown in mice that long-term caloric restriction can attenuate age-related immunosenescence on par with antibody-mediated clearance of senescent T-cells. On top of that, caloric restriction predictably improved glucose tolerance and lowered inflammation [1].

Senescent cells: inflamed and half-dead

Immunosenescence is an umbrella term for a variety of largely detrimental changes that our immune system undergoes as we age. It is tightly linked to inflammaging [2] – the smoldering background inflammation that is thought to be one of the major drivers of numerous age-related diseases. It is known, for example, that centenarians, most of whom are unusually healthy, experience significantly less inflammaging than “ordinary” elderly people.

With age, more memory T-cells express the protein ominously named programmed cell death protein 1 or PD-1. This subset of T-cells is also known as senescence-associated T-cells (SA-T cells), because they barely proliferate and produce large quantities of proinflammatory cytokines. The same group of scientists previously found that SA-T cells cause inflammation in visceral adipose tissue (VAT). VAT inflammation is strongly associated with various age-related diseases, on a larger scale than inflammation in subcutaneous fat.

With calories, less is more

Caloric restriction (CR), one of the most powerful and readily available anti-aging interventions known to us, can produce effects similar to centenarians’ genetics, lowering age-related inflammation and boosting healthy immune response.

In previous studies, scientists were able to ameliorate metabolic disorders in obese mice on high-fat diet by clearing out SA-T cells in VAT. This time, the researchers tried to evaluate the effect of long-term CR on the SA-T cells’ subpopulation and on glucose tolerance, another important marker of health linked to chronic inflammation [3].

First, the researchers examined their mice and found, rather unsurprisingly, that older mice weighed more and had more VAT than the younger ones – the problem of age-related abdominal fat accumulation that is well-known to humans. Aged mice also suffered from impaired glucose tolerance and insulin resistance.

SA-T cells taken from the spleen and the VAT of aged mice and of younger obese mice on a high-fat diet exhibited the familiar senescence-associated phenotype. Aged mice and obese mice also had more of these cells than normally fed mice.

In contrast, mice subjected to long-term CR had much lower body weight, less VAT, and improved glucose tolerance and insulin resistance than normally fed age-matched mice, not to mention obese mice.

CR decreases immunosenescence

The researchers found that long-term CR in mice also significantly reduced the burden of SA-T cells in the VAT. To rule out a non-causative correlation, the researchers then depleted the number of SA-T cells in a new group of mice using PD-1 antibodies. The clearing out of SA-T cells largely recapitulated the effects of CR, improving glucose tolerance and attenuating insulin resistance. The antibody treatment also substantially decreased the expression levels of most proinflammatory cytokines in VAT.

We demonstrated that the SA-T cell subpopulation increased with advanced age in the spleen, and age-related adiposity was associated with an accumulation of SA-T cells in eVAT. Long-term CR prevented this age-related adiposity and improved insulin resistance in aged mice. Furthermore, selective reduction of PD-1+ T cells by specific antibody treatment attenuated adipose inflammation and improved insulin resistance in aged mice. Taken together with our previous report, we concluded that the emergence of SA-T cells is a common molecular pathway in the development and progression of VAT inflammation and insulin resistance in the context of both chronological aging and obesity.

The mechanism by which the number of SA-T cells increase with age remains largely unknown. The researchers suggest that the appearance of these senescent-like cells has a lot in common with other types of cellular senescence and is caused, at least in part, by DNA damage. Cells often respond to DNA damage by becoming senescent in order not to proliferate the altered genotype, which helps to protect against cancer. CR is known to suppress oxidative stress, a major cause of DNA damage, which might be the main reason behind the CR-mediated decrease in T-cell immunosenescence.


Caloric restriction continues to prove its worth in one study after another. It is amazing how many age-related symptoms can be attenuated by CR, including, apparently, the accumulation of senescent immune cells. With the advance of senolytics, scientists need to find good targets for this novel class of drugs, and SA-T cells might become such a target, although more research for more tissue types is needed. Of course, while drugs that mimic the effects of CR are still in development, we can enjoy the benefits of the real thing by eating less and healthier.

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[1] Yan, X., Imano, N., Tamaki, K., Sano, M., & Shinmura, K. (2021). The effect of caloric restriction on the increase in senescence-associated T cells and metabolic disorders in aged mice. Plos one, 16(6), e0252547.

[2] Paudel, S., Sharma, P., & Puri, N. (2019). Immunosenescence, inflammaging, and their implications for cancer and anemia. In Models, Molecules and Mechanisms in Biogerontology (pp. 297-319). Springer, Singapore.

[3] HΓ€llgren, R., & Berne, C. (1983). Glucose intolerance in patients with chronic inflammatory diseases is normalized by glucocorticoids. Acta medica Scandinavica, 213(5), 351-355.

About the author
Arkadi Mazin

Arkadi Mazin

Arkadi is a seasoned journalist and op-ed author with a passion for learning and exploration. His interests span from politics to science and philosophy. Having studied economics and international relations, he is particularly interested in the social aspects of longevity and life extension. He strongly believes that life extension is an achievable and noble goal that has yet to take its rightful place on the very top of our civilization’s agenda – a situation he is eager to change.
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