Cellular senescence is one of the root causes of aging, and there are at present serious, well-funded efforts underway to produce rejuvenation therapies based on the selective destruction of senescent cells in old tissues. This progress is welcome, but it could have started a long time ago. It has taken many years of advocacy and the shoestring production of technology demonstrations to finally convince the broader community of scientists and funding institutions that the evidence has long merited serious investment in treatments to clear senescent cells. This is what it is, and now we must look to the future, for all that it has been a long, uphill battle. Cellular senescence is today having its time in the sun. Many research groups are linking the mechanisms of senescence to other aspects of aging; senescent cells are showing up in many more research papers than in past years, now that there is more of a scientific and financial incentive to search carefully for their influence. I think that declaring cellular senescence to be the causal nexus of aging, as one research group did, is going overboard a little, as there are, after all, other independent causes of aging, forms of metabolic waste and damage that would cause death and disease even if cellular senescence did not exist. Nonetheless, it is gratify to watch the spreading realization that cellular senescence plays a role in many areas of health and biology associated with aging. The advent of therapies that can remove senescent cells promises to produce sweeping beneficial effects on aging and disease.
There is a set of fairly well established threads of research that link aging with visceral fat tissue and immune dysfunction in the form of chronic inflammation. Visceral fat produces an accelerated pace of aging by generating greater chronic inflammation, producing an hostile tissue environment of inappropriate signals that attract immune cells and then cause those cells to become dysfunctional. The more fat there is the more inflammation it creates. This is thought to be the primary mechanism by which obesity increases the risk and severity of age-related disease. All of the common age-related diseases are accelerated in their progression by higher levels of chronic inflammation. The material difference between a lot of fat and a normal amount of fat is well demonstrated by a study in which researchers produced life extension in mice through surgical removal of visceral fat, but there is a mountain of data on human health to show that people who are overweight will suffer a shorter life expectancy and more age-related illness, and that this effect scales by the amount of excess fat tissue. How do senescent cells fit into this picture? One of the characteristic features of senescent cells is that they produce greater levels of chronic inflammation via the secretion of signal molecules such as cytokines. Of late, researchers have shown that senescent cells are found in the immune system, as in other cell populations. Given this, it should not be a surprise to find that cellular senescence can be implicated in the way in which visceral fat accelerates aging: their presence in visceral fat tissue and the immune cells interacting with that tissue fits right in with the broader picture of inflammation and bad cellular behavior.
Visceral obesity is associated with chronic low-grade inflammation in visceral adipose tissue (VAT) and a sustained whole-body proinflammatory state, which may underlie metabolic and cardiovascular diseases. VAT inflammation associated with obesity involves a complex network of responses of immune cell components, including acquired immune cells such as various subsets of T cells and B cells and innate immune cells such as macrophages. Among these cells, CD4+ T cells have been recognized as a central regulator of chronic VAT inflammation. The number of CD4+ T cells in VAT increases as the tissue expands in obesity. Factors that drive CD4+ T cell expansion and into proinflammatory effectors in VAT during the development of high-fat diet-induced (HFD-induced) obesity may include MHC class II-associated antigens, possibly self-peptides, because the T cell receptor (TCR) repertoire of CD4+ T cells in VAT is limited, and deficiency of MHC class II protects mice from high fat diet (HFD)-induced VAT inflammation and insulin resistance. However, the obesity-associated immune background underlying chronic inflammation in VAT remains elusive.
Significant changes occur in the overall T cell populations with age. In CD4+ T cells, proportions of naive (CD44loCD62Lhi) cells sharply decline in ontogeny, with an age-dependent increase in cells of the memory phenotype (CD44hiCD62Llo). Among CD44hiCD4+ T cells, a unique population expressing programmed cell death 1 (PD-1) and CD153 actually increases with age in mice. The CD153+PD-1+CD44hiCD4+ T cell population shows compromised proliferation and regular T cell cytokine production on T cell receptor (TCR) stimulation but secretes large amounts of proinflammatory cytokines, such as osteopontin. These CD4+ T cells also show signatures of cell senescence, including a marked increase in senescence-related gene expression and nuclear heterochromatin foci, and are termed senescence-associated T cells (SA-T cells). Notably, the age-dependent development of SA-T cells, which may include autoreactive cells, is dependent on B cells. As such, the increase in SA-T cells is suggested to be involved in part in immune aging phenotypes such as impaired acquired immune capacity, increased proinflammatory traits, and high risk for autoimmunity.
In the present study, we demonstrate that CD153+PD-1+CD44hiCD4+ T cells are remarkably increased and preferentially accumulated in the VAT of HFD-fed mice in a B cell-dependent manner and that these CD4+ T cells show functional and genetic features strongly resembling SA-T cells that increase in secondary lymphoid tissues with age. We also indicate that the CD153+PD-1+CD44hiCD4+ T cells play a crucial role in inducing chronic VAT inflammation and metabolic disorder via secretion of large amounts of osteopontin. We demonstrated that adoptive transfer of CD153+PD-1+CD44hiCD4+ T cells, but not other CD4+ T cells, from HFD-fed spleens into VAT of ND-fed mice recapitulates the features of VAT inflammation, including a striking increase in CD11chiCD206lo macrophages and expression of proinflammatory cytokine genes. It is noteworthy that CD153+PD-1+CD4+ T cells in VAT of HFD-fed mice show features indistinguishable from those of CD153+ SA-T cells, which gradually increase systemically with age. The age-dependent increase in CD153+ SA-T cells may partly underlie the immune aging, including a reduction in acquired immunity and an increase in the inflammatory trait and autoimmunity risk. Obesity is also associated with diminished resistance against infection, chronic low-grade inflammation, and a greater susceptibility to autoimmunity. It has been suggested that the increase in CD153+ SA-T cells in chronological aging and systemic autoimmunity is attributable to a robust, homeostatic T cell proliferation, but the precise mechanism underlying the accumulation of these T cells in VAT of HFD-fed mice remains to be investigated. Nonetheless, it is an intriguing possibility that the predisposition often associated with obesity may partly be a systemic manifestation of the premature increase in CD153+ SA-T cells in VAT, since adipose tissues can constitute up to 50% to 60% of total BW in severe obesity.