The study, from a team of researchers at the University of Minnesota, found that aging of immune cells not only leads to impaired immune function, but also promotes damage to other non-immune organs and leads to shorter life spans in mice.
Transplanting senescent immune cells also promotes aging and tissue damage; conversely, transplanting “young” immune cells can reverse aging to some extent.
So …… who has young and strong immune cells, please share them!
Why is the study of aging being studied on immune cells?
In recent years, scientists have actually realized that since aging is a major risk factor for most chronic diseases, aging itself could be a possible target for treatment.
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To treat aging, the actual operation falls on senescent cells. Senescent cells are a special class of cells that have largely ceased to proliferate but retain metabolic activity, and are characterized by a senescence-associated secretory phenotype (SASP) that secretes inflammatory cytokines, growth factors and proteases. A small number of senescent cells can lead to the decline of the body’s function.
Scientists have developed a series of drugs to target senescent cells, called senolytics, and they have also shown some effect in preclinical studies.
But there are some problems with this idea. Not only can’t we get rid of all senescent cells in one go, but even if we could, the safety profile would be poor. Then a new solution emerged – which senescent cell is the biggest driver of aging, we hit it first!
Thus, researchers came up with immunity.
Along with the aging of the organism, the immune is aging as well, which limits resistance to pathogens and cancer cells and is why older people are more susceptible to disease and less sensitive to vaccines.
If immune aging can be addressed first, it should be very helpful in defeating overall aging.
Here, the researchers used specific knockdown of ERCC-1, a key enzyme for DNA repair, to “age out” the immune system in mice, and previously showed that reduced expression of ERCC-1 impeded DNA damage repair and led to the accumulation of multiple oxidative damages and senescent cells .
Although mice were knocked out of ERCC-1 in their immune organs, they were still able to be born and grow up normally and did not show any difference until adulthood. However, when tested at 8-10 months of age, a significant increase in the level of oxidative DNA damage in the spleen and bone marrow tissues of the mice can be observed.
Knockout ERCC-1 mice had significantly lower numbers of T and B cells when compared longitudinally to their younger selves; knockout mice also had more erratic lymphocyte counts when compared horizontally to normal mice. The researchers believe that this is enough to suggest that what is happening in ERCC-1 knockout mice is not a “developmental defect” in immunity, but rather a “degeneration” of immunity.
To put it more colloquially, the immune system of ERCC-1 knockout mice is aging prematurely!
When compared to normal 2-year-old senescent mice, the immune cells of the knockout mice were also found to be somewhat similar to naturally senescent immune cells. Subsequent analysis of immune cell subsets also showed that knockout mice had significantly increased SASP phenotypes of T cells, NK cells and macrophages, similar to normal senescence.
Compared to normal mice (blue), the immune cell profile of ERCC-1 knockout mice (red) is similar to that of normal senescent mice (yellow)
So what are the effects of aging of the immune system?
Decreased immune function is a sure thing. The researchers also collected a variety of tissues from 8-11 month old knockout mice for analysis and found high levels of DNA damage, oxidative stress and senescence in non-lymphoid organs as well!
These in turn led to further tissue damage. Examples include elevated serum levels of alanine and aspartate aminotransferases, markers of liver damage, elevated urine levels of albumin and markers of kidney damage, and elevated levels of amylase, a marker of pancreatic dysfunction.
Needless to say, ERCC-1 knockout mice also had shorter lifespans.
Multiple tissues exhibit aging and damage
Mice with aging immune systems have shorter lifespans
When the researchers transplanted splenocytes from ERCC-1 knockout mice to prematurely aged model mice, the poor mice were even more decrepit and lived even shorter lives.
Conversely, when splenocytes from young healthy mice were transplanted to prematurely aged mice, testing one month later revealed a significant reduction in the expression of aging markers in several tissues and a decrease in SASP-associated cytokines in the blood circulation.
Significant reduction in cellular senescence characteristics after transplantation of immune cells from young mice (orange)
Previous studies found that inhibition of mTOR activity with rapamycin analogs enhanced the response to influenza vaccine in the elderly , so the investigators also tried to treat ERCC-1 knockout mice with rapamycin and found that it significantly reduced the expression of senescence markers in peripheral immune cells and improved immune function in mice.
This shows that targeting senescent immune cells is indeed promising.