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A Study of Early Life Adversity versus Later Immune Aging Points to Cytomegalovirus as the Problem

A fair number of research groups study psychological stress and aging, and investigations of early life adversity versus later risk of age-related disease fall into this category. The paper here finds that persistent cytomegalovirus infection is likely the mediating mechanism linking early life stress and later increased risk of age-related disease, acting through accelerated immune system dysfunction. This implies that the early stress may or may not be all that important, as - for whatever reason - the groups selected as examples of stress in early life are also more likely to be infected. That might be the short-term detrimental effects of stress on immune function, or it could be a matter of being in close contact with more distinct groups of people during childhood, as is the case for the adopted individuals in the study here.

Cytomegalovirus is a persistent herpesvirus that the immune system cannot effectively clear from the body. Near everyone becomes infected at some point in life, and extensive evidence links this infection with immune system dysfunction. Increasing numbers of immune cells become dedicated to uselessly fighting cytomegalovirus, and ever fewer are left for everything else the immune system must accomplish. Other than this long-term corrosion, cytomegalovirus doesn't cause obvious symptoms in the vast majority of people - few notice the initial infection. Removing cytomegalovirus isn't that helpful, as the damage is already done in the old, and the young will be reinfected. A more useful approach might be to selectively target and destroy cytomegalovirus-specific immune cells to free up space for their replacement.

Adverse and stressful events in childhood, such as parental loss, low childhood socioeconomic status, or institutionalization, have been associated with elevated levels of inflammation and an increased risk for multiple age-related diseases, such as cardiovascular disease. Many efforts have been made to understand the mechanisms underlying long-term effects of ELA. One of the mechanisms proposed is accelerated aging of the immune system, also known as immunosenescence. Immunosenescence refers to the process of progressive deterioration of immune functions that go hand in hand with normal aging. If ELA affects the rate of immunosenescence, this may explain an increased risk and earlier onset of age-related disorders.

It remains an open question as to what drives ELA-associated immunosenescence. Besides ELA, several other environmental factors have been found to modulate the rate of immunosenescence, such as persistent viral infections. Herpes simplex virus (HSV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) are among the most prevalent viral infections that establish latency after primary infection and reactivate when the immune system is compromised. Latent infections with CMV in particular are believed to play an important role in immunosenescence and are associated with age-related alterations of T cell immunity.

In this study, we investigated T cell-specific immunosenescence (T cell differentiation and CD57 expression) in participants with and without a history of ELA. Participants in the ELA group had experienced separation from their parents in early childhood and were subsequently adopted, which is a standard model of ELA. This study cohort is a healthy subset of the EpiPath cohort, excluding all participants with acute or chronic diseases. With a mediation analysis we examined whether CMV titers may account for immunosenescence observed in ELA.

In this study, we have shown that ELA is associated with higher levels of T cell senescence in healthy participants. Not only did we find a higher number of senescent cells (CD57+), these cells also expressed higher levels of CD57, a cell surface marker for senescence, and were more cytotoxic in ELA compared to controls. Control participants with high CMV titers showed a higher number of senescent cells, compared to controls with low titers. Importantly, we found that the effect of ELA on immunosenescence was associated with CMV infection specifically, rather than being the consequence of continued reactivation of latent viruses in general.

Our findings have important implications for this literature on senescence in ELA. Most evidence for accelerated immunosenescence in ELA comes from telomere length, but none of these studies have accounted for CMV infections. Our results suggest that the association between ELA and shorter telomeres - or immunosenescence in general - may have been largely mediated by CMV infection. First of all, because there is a clear link between CMV infection and immunosenescence. CMV infection is related to expanding populations of specific memory T cells, and a shrinking population of naïve T cells, similar to what is observed in aging. CMV seropositivity has been shown to reduce life expectancy by almost 4 years in an elderly population, especially due to an increase in cardiovascular deaths.

Second, there is reason to believe that children in adverse circumstances are at higher risk for CMV infection. For instance, the likelihood of CMV infection is higher in children raised in poverty and low socioeconomic status. There is no clear epidemiological data on the prevalence of infection in international adoptees, as were included in this study. However, most adopted children have been institutionalized prior to adoption, which arguably increases the risk for CMV infection, as is the case for day-care center attendance.

Link: https://doi.org/10.3389/fimmu.2017.01263

Comments

Valacyclovir taken daily would seem to be helpful in this situation as it can remove EBV after a number of years and decreases the frequency of reactivation occurrences of HSV and CMV.

Posted by: Jake at November 13th, 2017 9:11 PM

Removing CMV is the sensible move here due to the increasing immunosurveillance it demands over time to keep it latent. Given that it proliferates using inflammation as its activation mechanism and that inflammation rises with age unless it is removed it will put increasing strain on the immune system. The ideal situation would be to engineer immune cells that are more effective at killing CMV fully. Removing CMV-specific immune cells is problematic as they are keeping CMV dormant and preventing it becoming fully activated.

Posted by: Steve Hill at November 14th, 2017 6:04 AM

@Steve - it's probably a big ask. But in the future I hope that lifespan.io are able to run a crowdfunded campaign to fund looking at using Oisin's non toxic lipposome technology to insert a suicide gene into cells that CMV genes expressed.

Or given that CAR T cells can be created with a receptor wii an antibody fragment on the end to detected cancer cell antigens, could someone not create a car T cell with an antigen used by regular and memory T cells to target cmv infected cell, using car T cells to clear out these excess T cells?

I supposed this is yet another case of the necessary research path being obvious, but obtaining the funding being anything but.

Posted by: Jim at November 14th, 2017 5:59 PM

I saw news today that the ability of the CRISPR-cas9 system to 'slash' genes in vivo was improved by using nano particles which don't elict an immune response like viruses, enabling mutliple dosing. And by having chemically modified RNA for the short guide RNA that survived longer in cells. They reckon that they slashed a gene in 80% of liver cells in vivo:

https://www.genengnews.com/gen-news-highlights/crisprcas9-delivery-goes-nano-with-enhanced-guide-rna/81255165

"According to the MIT team, which was led by Daniel G. Anderson, Ph.D., an associate professor of chemical engineering and a member of MIT's Koch Institute, the new delivery technique cut out certain genes in about 80% of liver cells, the best success rate ever achieved with CRISPR in adult animals."

So maybe the CRISPR-cas9 system could be used to slash CMV genes throughout the body, provided off target effects can be limited enough:

https://en.wikipedia.org/wiki/Herpes_simplex_research#Notable_research

"Notable research

The Jerome Lab run by Dr. Keith Jerome at the Fred Hutchinson Cancer Research Center has looked at using zinc finger nuclease as well as endonuclease to prevent HSV from replicating. Most recently Dr. Jerome and his lab were able to demonstrate cleavage of latent HSV in a living organism, which is vital to disabling the virus. The lab is now looking at ways to better optimize the process, including using CRISPR-Cas9, with several years of work expected before clinical trials are considered.

CRISPR-Cas9 is presently being researched for its use for Herpes simplex keratitis by Editas Medicine to advance the technology.

Researchers at Temple University have been researching how to disrupt HSV from replicating that could eventually lead to a cure. Some members of research team at Temple University have also joined forces to create Excision BioTheraputics. The company intends to begin clinical trials in 2018."

Posted by: Jim at November 14th, 2017 9:32 PM

Jim: I would like to see DRACO funded. It would be better than having only a CMV-specific therapy.

Posted by: Antonio at November 15th, 2017 12:19 AM

As we wait for technology to provide solutions:

Green tea suppresses much viral replication.

Also, I am of the opinion that most diseases of aging are related to too much dietary methionine. It seems that the "Blue Zones" centenarians have in common low or very low protein intake.

Methionine dependence of virus-infected cells

https://www.sciencedirect.com/science/article/pii/001448279090199K

Posted by: Lee at November 15th, 2017 6:54 AM

Methionine is vital to DNA replication. Restricting it reduces MTOR so slows down proliferation. So yet this will slow down aging. Almost impossible to remove this from your diet however. More generally lowering protein is doable, but again this is only slowing aging and will not give you more than calorie restriction.

Posted by: Mark at November 15th, 2017 7:52 AM

@Mark
I am advocating (and practicing) reducing methionine not eliminating.
Excess methionine is associated with many of the diseases of aging so it is virtuous for healthspan and lifespan.
Why suffer with CR when you can limit methionine consumption or do time restricted feeding or time restricted feeding with methionine restriction?

Posted by: Lee at November 15th, 2017 7:08 PM

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