Correlating Cytomegalovirus, T Cell Senescence, and Arterial Stiffness in Aging
Today I'll point out a paper that links three fairly long-standing topics in aging research: the role of cytomegalovirus infection in immune system aging, cellular senescence in the immune system, and progressive stiffening of blood vessels. The authors point out correlations rather than uncovering specific mechanisms to link these items, but it fits nicely with a range of other research on senescent T cells, ways in which senescent cells could contribute to loss of vascular elasticity, the decline of the aging immune system, and the intricate relationship between tissue maintenance and immune system activity. Disarray in regeneration is linked closely with disarray in the immune system, particularly the chronic inflammation that occurs with age. To complete the circle, in any scenario involving inflammation in aging, we nowadays have to pull in the topic of senescent cells for consideration. These cells are efficient generators of inflammatory signaling, and this appears to be a primary mechanism by which they cause harm.
Blood vessel stiffness is one of the most consequential aspects of aging. Cardiovascular disease vies with cancer for the most prevalent cause of death in our species. Stiffness in blood vessels produces hypertension, which in turn contributes to the remodeling of heart tissue that leads to heart failure. Hypertension and stiffness also increase the pace at which small vessels rupture in the brain, and other delicate organs such as the kidney, raising the pace of damage in those tissues. Finding ways to maintain blood vessel elasticity would go a long way to reduce the incidence of numerous classes of age-related disease.
Where does cytomegalovirus fit into this? This is a herpesvirus that is present in near everyone by the time old age rolls around. It is largely harmless to most people, at least in the short term, but over the long term the immune system just keeps on throwing resources at cytomegalovirus in a futile attempt to get rid of it. In an aged immune system a vast number of cells are uselessly specialized to cytomegalovirus, rather than being available for other tasks. The rate of replacement of immune cells is low in adults, and even lower in the elderly, and thus the immune system cannot recover from a state in which most active immune cells are not performing as they should. At least not without some form of outside intervention yet to be brought to the clinic, such as regeneration of the thymus, or regular infusions of patient matched immune cells grown from skin samples.
A correlation between the degree to which the immune system is engaged in its eternal losing battle with cytomegalovirus and the number of senescent T cells suggests a causal relationship, though given the present state of the field I think that a decent argument could be made for the arrow of causation to point in either direction. Are those elders most afflicted by cytomegalovirus afflicted because the immune system was already in a state of accelerated decline for other reasons, or is cytomegalovirus the cause of that decline? From historical data and comparisons between regions of today's diverse world we know that a greater burden of infectious disease has a negative impact on life expectancy. So it is tempting to look first for cytomegalovirus to be the cause, but biology is rarely as consistent as we'd like it to be.
Arterial Stiffness Is Associated With Cytomegalovirus-Specific Senescent CD8+ T Cells
Growing evidence from recent animal and human studies suggests that T cells contribute to the development of hypertension. Previously, we demonstrated that hypertensive patients have an increased frequency of replicative senescent CD8+ T cells in peripheral blood; these cells are characterized by the loss of CD28 and the acquisition of CD57 on their surface. CD28 loss in T cells is one of the most prominent changes associated with aging in humans and is caused by the repetitive antigenic stimulation of T cells. CD57 expression is known to occur during the late stage of T-cell differentiation and might be a distinct measure of replicative senescence in T cells. Compared with CD28+ or CD57- T cells, CD28null or CD57+ T cells produce more proinflammatory cytokines and exert greater cytotoxicity. These senescent T cells are known to be associated with various inflammatory diseases in humans including cardiovascular disease.
It has been also known that cytomegalovirus infection is involved in the accumulation of CD28null or CD57+ senescent T cells. In humans, cytomegalovirus is known to be one of the most important antigens for repetitive T-cell stimulation, and latent infection with cytomegalovirus has been shown to strongly exert age-associated changes on peripheral T cell homeostasis. The cytomegalovirus-seropositive population has a higher frequency of CD28null or CD57+, replicative senescent T cells than the cytomegalovirus-seronegative population. Moreover, cytomegalovirus infection is associated with a variety of chronic inflammatory processes in cardiovascular disease such as hypertension. However, it has not been elucidated how cytomegalovirus infection and senescent T cells contribute to the pathogenesis of cardiovascular disease.
Increased arterial stiffness is one of the major mechanisms underlying the pathogenesis of hypertension. Arterial stiffness is increased in the presence of conventional cardiovascular risk factors including aging. The degree of arterial stiffness is known to be associated with various markers of inflammation, suggesting that immune responses likely play a role in increasing arterial stiffness. Therefore, we investigated whether T-cell senescence is associated with arterial stiffness in the general population, as assessed using pulse wave velocity (PWV) measurements. Next, considering the antigen reactivity of senescent T cells, we examined cytomegalovirus-specific T-cell response and analyzed the relationship between these results and the degree of arterial stiffness.
The study population consisted of 415 Koreans who were recruited from subjects initially registered in the Yonsei Cardiovascular Genome cohort. Our findings demonstrate that the frequency of senescent CD8+CD57+ T cells in peripheral blood is independently correlated with arterial stiffness. Cytomegalovirus-specific T-cell responses were analyzed because cytomegalovirus is a major driving antigen for replicative senescence in T cells. We found that cytomegalovirus-specific CD8+ T cells were more frequently observed in the CD57+ population, and cytomegalovirus-specific cytokine secretion and the cytotoxic degranulation of CD8+ T cells were independently associated with PWV. These data suggest that immune aging, especially T-cell senescence that is linked to cytomegalovirus infection, might play a role in the progression of vascular aging.
Regarding regeneration of the Thymus, as most reading this are probably aware, back in 2014 it was demonstrated that turning on FOXN1 in the mouse thymus caused it to regenerate.
That demonstration used germline genetically engineered mice to turn on FOXN1 in the thymus using a small molecule drug.
"To this end, she and her colleagues bred a special strain of mice whose FOXN1 production could be stimulated specifically in the thymus by tamoxifen, a drug more familiar as a treatment for breast cancer."
But yesterday I read about the Fred Hutch developing an 'easy' mRNA gene therapy platform - New nanoparticles make targeted, temporary gene therapy possible.
"Now, Stephan has brought together the best of both methods in a gentle, targeted and transient technique. The nanoparticles are formed by bundling synthetic messenger RNA (modified to be safer and more stable than natural RNA) into miniscule packages surrounded by a biodegradable coat. The coat itself is studded with molecules that help the nanoparticles home in on exactly the right cell type.
The researchers showed that hours after the nanoparticles are taken up by target cells, the cells begin churning out proteins based on the new messenger RNA they've received. Then, within days, production ceases as the messenger RNA degrades."
If there are already distinct receptors on thymic cells, then these nanoparticles could be targeted to the thymus using these markers. But in the short term someone could just inject nanoparticles with FOXN1 mRNA directly into a mouse thymus.
Would this be an experiment worth doing? Would SENS be able to get a summer intern on this? Could the MMTP look at doing this through lifespan.io?
We are open to a discussion via LEAF for a project. Perhaps this is something SENS would like to test?
I wonder if Clare Blackburn of Edinburgh University (who conducted the original FOXN1 study) is now studying a somatic gene therapy approach?
Very interesting Jim, could this be the delivery method we've been waiting for to enable somatic gene therapy?
@Mark - Well I'm a layperson, so I really don't know. All I have to go on are the press articles. It certainly sounds great. Oisin's fusogenic lipid nanoparticles sound pretty good too.