Senescent T Cells Generate the Same Damaging Secretions as Other Senescent Cells
The immune system runs awry with age in a number of overlapping ways. The adaptive component of the immune system, made of B cell and T cell populations that adapt to store information about the pathogens they encounter, in particular suffers from forms of misconfiguration and exhaustion. Too many cells become devoted to useless tasks, such as the continually expanding and pointless battle against cytomegalovirus. Too much activity against pathogens produces large numbers of exhausted T cells and anergic T cells, incapable of responding aggressively when reacting to new threats, and not replaced rapidly enough with fresh T cells. Aging is accompanied by a diminished capacity to generate new T cells; this limit squeezes down from the top, while the failure and overspecialization of T cells squeezes up from the bottom. The immune system becomes ever less capable.
Because the T cell response to invaders involves replication, the rapid creation of a suitably equipped army to fight whatever the current war might be, there will always be some degree of cellular senescence in T cells, just as in all replicating cell types in the body. Cellular senescence is one of the full stops at the end of a normal cell's life span: it can only divide so many times before its telomeres become short, it hits the Hayflick limit, and either self-destructs or becomes senescent. Senescent cells near all go on to self-destruct a little later, or are destroyed by portions of the immune system dedicated to that purpose. Senescence can also be triggered by DNA damage resulting from a toxic environment, other forms of severe cellular stress, or the signals of nearby senescent cells. This serves to suppress the risk of cancer by removing those cells most likely to gain the combination of mutations needed to run amok. Senescent cells also have some transient, beneficial activities: they are involved in wound healing and embryonic development, again being destroyed after their task is complete.
Unfortunately some senescent cells linger for the long term, evading destruction. I say unfortunately because senescent cells generate a potent mix of inflammatory and other signals, the senescence-associated secretory phenotype (SASP). This disrupts regenerative processes, corrodes nearby tissue structures, and spurs the chronic inflammation that drives so many of the aspects of aging. While only a few percent of all cells have become senescent by the time old age rolls around, that is more than enough to have caused a significant fraction of the medical conditions of degenerative aging. Researchers have shown that senescent cells are one of the direct significant contributing causes of a wide range of issues: the ultimately lethal fibrosis that occurs in many organs; osteoarthritis; atherosclerosis; and more.
In the research noted here, the authors show that senescent T cells have essentially the same SASP as other forms of senescent cells investigated in recent years. This means that they will be just as harmful to health, a cause of aging given sufficient numbers. It is something of a debated question as to how much of T cell dysfunction with age is a matter of anergy, exhaustion, or senescence, and so also a question as to how many of these cells there are. If the numbers are significant, their presence also means that efforts to selectively remove senescent cells by provoking them into apoptosis, or by identifying their specific internal chemistry, should be expected to improve immune function alongside the other benefits shown to date in animal studies. Clearing out broken, dysfunctional T cells will free up space in the immune system and trigger their replacement. That will happen slowly in old people, given the limited replacement rate, but that too can be improved with suitable cell therapies - delivering large numbers of patient-matched immune cells is well within the present capacities of the biotechnology industry, just another of a fair number of potential treatments that have yet to be pushed through the regulatory system. Too many possibilities, too few researchers, and too high a regulatory barrier to entry.
Human CD8+ EMRA T cells display a senescence-associated secretory phenotype regulated by p38 MAPK
Immune senescence results from defects in T-cell immunity and is also characterized by a low-grade chronic inflammatory state. Little is known about the source of the inflammation that fuels most age-related diseases; however, it may derive from an age-related decline in homoeostatic immune function, resistance to endogenous microbes or senescent cells. The senescent phenotype is not just proliferative arrest; rather, it is a widespread change in protein expression and secretion, including pro-inflammatory cytokines, chemokines, growth factors and proteases, termed the senescence-associated secretory phenotype or SASP. Consequently, senescent cells can alter the tissue microenvironment and affect neighbouring cells through paracrine signalling.
The SASP was originally thought to result from persistent activation of the DNA damage response; however, it is now known to be regulated by p38 MAPK, which was shown to be both necessary and sufficient for its development in fibroblasts. The chronic and sustained activation of p38 MAPK differs substantially from the response to acute stress and was found to follow the kinetics of SASP development. Furthermore, siRNA interference of p38 MAPK was shown to significantly reduce the secreted levels of most SASP factors. To date, the SASP has predominantly been characterized in fibroblast cell culture models or aged mice, with very few reports of a SASP being found in the human immune system with either age or differentiation.
Senescent CD8+ T cells are found within the CD27-CD28- population, and these highly differentiated T cells can be further divided using CD45RA. T cells that re-express CD45RA within this subset have multiple characteristics of senescence, including a low proliferative activity, high levels of DNA damage and the loss of telomerase activity. We have also shown that p38 MAPK signalling, which is increased in highly differentiated CD8+ T cells, is involved in the loss of telomerase activity and proliferative capacity and that blockade of p38 MAPK activity with a specific small-molecule inhibitor can restore both proliferation and telomerase activity in these cells. However, surprisingly the CD45RA-re-expressing senescent T cells do not have critically short telomeres, suggesting that senescence in these cells may be induced by other mechanisms including DNA damage by increased reactive oxygen species production.
In this study, we demonstrate that irrespective of the derivation of CD8+ CD45RA+CD27- T cells, these primed cells exhibit a unique highly inflammatory secretory profile characteristic of the SASP, and we also provide evidence that ADAM28 can be used as a functional marker of senescence in CD8+ T cells. Furthermore, we show that the secretory phenotype in CD8+ CD45RA+CD27- T cells is controlled through p38 MAPK signalling, which contributes to age-associated inflammation.
It isn't a pointless battle against CMV because T cells keep CMV in check and suppress reactivation so they are serving a purpose. It is an ultimately hopeless battle though, that is for sure. CMV can take up to 10% of T cell population because of the systemic nature of CMV so it is a huge problem that needs dealing with as microbial burden drives inflammaging.
I think we need two major ways of rescuing our aging immune system. First, we need a way of getting rid of the senescent T cells by apoptosis either by activating the genes that remove the senescent cells, such as various sirtuins, especially, SIRT1, SIRT3, and SIRT6, and other genes like FOXO3A. We also need a new source of T cells when the telomeres get too short to provide them. OBFC1 is a gene that activates telomerase to leukocyte telomeres by 230 to 290 base pairs (Levy, 2010), that is enough to sustain the leukocytes about 10 years, since 20-30 base pairs are eroded per year. The active SNP's and alleles involved are OBFC1 rs9420907 AA, rs2487999 CC, and 9419958 CC. Another gene that activates leukocyte telomeres and lengthens them is ADA rs73598374 CC. The TNFa gene works synergistically to increase leukocyte telomere length and longevity of those who have the following TNFa SNP alleles, rs1800629 GG and rs361525 GG. I happen to be homozygous for all of the longevity SNP's I have listed above, and am also homozygous for the longevity alleles of many FOXO3A (at least 12 of them), and for at least some of the sirtuins. If you don't have the longevity alleles of these genes, perhaps in the future with CRISPR technology, they can be transplanted to your genome.
In my above post, reference sources for the ADA gene are Concetti, 2013, and Napolioni, 2015.