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Dean Pomerleau posted a topic in General Health and LongevityAll, Over on the thread Common Chronic Viral Infections Linked to Cognitive Decline we've seen how cytomegalovirus (CMV) is associated with immunosenescence, atherosclerotic plaques, and cognitive decline. It appear the body's immune system gets worn out (i.e. immune system stem cells get depleted) by trying in vain to eliminate chronic CMV infection. This heighted immune response results in systemic inflammation, increased plaque formation in arteries and reduced blood flow to the brain, triggering cognitive decline. Overall bad news. The news is made even worse by the fact that between 50 and 80% of people are infected with cytomegalovirus by age 40! And in the elderly, the typical infection rate can be upwards of 95%... But the real kicker, and the reason for this new thread devoted to CMV, is this study , ominously titled Cytomegalovirus infection accelerates epigenetic aging, which was covered this week in a blog post by Reason over at FightAging! In the study, they looked at the CMV status of two sets of people - some their 20s and some in their 90+ and correlated CMV status with "epigenetic age" as measured by "clock like" changes in DNA methylation that appear to happen as people age. This epigenetic age metric has been shown in several studies to correlated with both physical and mental fitness , and with mortality rate . For example Marioni et al.  observed that 69–79 year old individuals had a 16% increased mortality during a 4–10 year follow-up if the epigenetic age was 5 years higher than the calendar age. What they found first was that 57% of the 20-somethings tested positive for CMV, and 95% of the nonagenarians tested positive - once again showing CMV infection is extremely common in the general population. Further, they found that in the younger cohort, being CMV-positive as associated with a 2.5 year increase in epigenetic age, and in the older folks, testing positive for CMV was associated with a 7 year increase in epigenetic age. But it gets worse. This 2011 study  found that in 14,000+ people age ≥25 from the NHANES III cohort, being CMV-positive was associated with an 20% increase in all-cause mortality over a ~16 year follow-up period. People who were both CMV-positive and had elevated C-reactive protein (> 3.0 mg/L) had it even worse - they were at a 30% higher risk of mortality relative to the (already mortality-challenged) CMV-positive folks with low CRP. Here is the graph of the data for all-cause mortality as a function of CMV status and CRP level ("high" CRP means ≥ 3.0 mg/L): Notice how simply being CMV-positive (even with low CRP) was dramatically worse for all-cause mortality risk than if you have a CRP of > 3.0 mg/L, but are free from CMV infection. How sucky is that? We try so hard to make sure our level of systemic inflammation (as measured by C-reative protein) is low. But it turns out having high CRP isn't nearly as bad for longevity as simply having a chronic CMV infection, which almost everyone has. In short, having what has long been thought to be a (relatively) harmless chronic infection with CMV appears associated with dramatic speeding up of the aging process and an increase in mortality risk. More bad news - once you've got CMV, you've got it for life. There are antiviral drugs to fight CMV given to people who have compromised immune systems and solid organ recipients, but they don't cure it and have nasty side effects like immune system suppression and kidney damage to boot. LEF offers tests for chronic CMV infection or acute CMV infection for $59 and $99 respectively (member pricing), but for those who've recently donated blood, you should be able to call your blood bank like I did to find out your CMV status for free. What can someone do to avoid contracting CMV if they are lucky enough not to have it already? It's passed via bodily fluids, so the best way to avoid contracting it is through practicing good hygiene, including: Wash your hands often. Use soap and water for 15 to 20 seconds, especially if you have contact with young children or their diapers, drool or other oral secretions. This is especially important if the children attend child care. Avoid contact with tears and saliva when you kiss. Instead of kissing on the lips, for instance, kiss on the forehead. This is especially important if you're pregnant. Avoid sharing food or drinking out of the same glass as others. Sharing glasses and kitchen utensils can spread the CMV virus. Be careful with disposable items. When disposing of diapers, tissues and other items that have been contaminated with bodily fluids, be careful not to touch your hands to your face until after thoroughly washing your hands. Clean toys and countertops. Clean any surfaces that come into contact with children's urine or saliva. Practice safe sex. Wear a condom during sexual contact to prevent spreading the CMV virus through semen and vaginal fluids. Given the serious apparent downsides of CMV infection, protecting my current CMV-negative status seems to me the most compelling reason to diligently adhering to this admittedly rather burdensome set of hygiene practices. --Dean -------  Exp Gerontol. 2015 Dec;72:227-9. doi: 10.1016/j.exger.2015.10.008. Epub 2015 Oct 17. Cytomegalovirus infection accelerates epigenetic aging. Kananen L(1), Nevalainen T(2), Jylhävä J(3), Marttila S(4), Hervonen A(5), Jylhä M(6), Hurme M(7). Full text: http://sci-hub.cc/10.1016/j.exger.2015.10.008 Epigenetic mechanisms such as DNA methylation (DNAm) have a central role in the regulation of gene expression and thereby in cellular differentiation and tissue homeostasis. It has recently been shown that aging is associated with profound changes in DNAm. Several of these methylation changes take place in a clock-like fashion, i.e. correlating with the calendar age of an individual. Thus, the epigenetic clock based on these kind of DNAm changes could provide a new biomarker for human aging process, i.e. being able to separate the calendar and biological age. Information about the correlation of the time indicated by this clock to the various aspects of immunosenescence is still missing. As chronic cytomegalovirus (CMV) infection is probably one of the major driving forces of immunosenescence, we now have analyzed the correlation of CMV seropositivity with the epigenetic age in the Vitality 90+cohort 1920 (122 nonagenarians and 21 young controls, CMV seropositivity rates 95% and 57%, respectively). The data showed that CMV seropositivity was associated with a higher epigenetic age in both of these age groups (median 26.5 vs. 24.0 (p < 0.02,Mann–Whitney U-test) in the young controls and 76.0 vs. 70.0 (p < 0.01) in the nonagenarians). Thus, these data provide a new aspect to the CMV associated pathological processes. DOI: 10.1016/j.exger.2015.10.008 PMID: 26485162 ------  Marioni, R.E., Shah, S., McRae, A.F., Ritchie, S.J., Muniz-Terrera, G., Harris, S.E., et al., 2015b. The epigenetic clock is correlated with physical and cognitive fitness in the Lothian birth cohort 1936. Int. J. Epidemiol. (doi:dyu277 [pii]) -------  Marioni, R.E., Shah, S., McRae, A.F., Chen, B.H., Colicino, E., Harris, S.E., et al., 2015a. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 16 (1), 25 (doi:s13059-015-0584-6 [pii]). -------  PLoS One. 2011 Feb 17;6(2):e16103. doi: 10.1371/journal.pone.0016103. Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States. Simanek AM(1), Dowd JB, Pawelec G, Melzer D, Dutta A, Aiello AE. Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21379581/ BACKGROUND: Studies have suggested that CMV infection may influence cardiovascular disease (CVD) risk and mortality. However, there have been no large-scale examinations of these relationships among demographically diverse populations. The inflammatory marker C-reactive protein (CRP) is also linked with CVD outcomes and mortality and may play an important role in the pathway between CMV and mortality. We utilized a U.S. nationally representative study to examine whether CMV infection is associated with all-cause and CVD-related mortality. We also assessed whether CRP level mediated or modified these relationships. METHODOLOGY/PRINCIPAL FINDINGS: Data come from subjects ≥ 25 years of age who were tested for CMV and CRP level and were eligible for mortality follow-up on December 31(st), 2006 (N = 14153) in the National Health and Nutrition Examination Survey (NHANES) III (1988-1994). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause and CVD-related mortality by CMV serostatus. After adjusting for multiple confounders, CMV seropositivity remained statistically significantly associated with all-cause mortality (HR 1.19, 95% CI: 1.01, 1.41). The association between CMV and CVD-related mortality did not achieve statistical significance after confounder adjustment. CRP did not mediate these associations. However, CMV seropositive individuals with high CRP levels showed a 30.1% higher risk for all-cause mortality and 29.5% higher risk for CVD-related mortality compared to CMV seropositive individuals with low CRP levels. CONCLUSIONS/SIGNIFICANCE: CMV was associated with a significant increased risk for all-cause mortality and CMV seropositive subjects who also had high CRP levels were at substantially higher risk for both for all-cause and CVD-related mortality than subjects with low CRP levels. Future work should target the mechanisms by which CMV infection and low-level inflammation interact to yield significant impact on mortality. DOI: 10.1371/journal.pone.0016103 PMCID: PMC3040745 PMID: 21379581
Michael R posted a topic in CR Science & TheoryAll: Rapamycin is by far the best-supported drug (or "drug-type" supplement) potential anti-aging therapy, as most or all of you should know; it is thought to work by inhibiting mTOR, thereby inhibiting protein synthesis and boosting autophagy. Its interactions with the mechanisms of CR in mammals are complex but seemingly not very overlapping, as discussed eg here , here, and most cogently in this context here, suggesting the tantalizing possibility that rapamycin might not be a "CR mimetic" as once thought, but engage a different anti-aging pathway that might be additive to or synergistic with CR mimetics or CR itself. The biggest heretofore-identified potential roadblocks to the use of rapamycin or some modified mTOR inhibitor as anti-aging interventions in humans are diabetic-like side-effects and immune suppression seen in patients given rapamycin for existing indications (mostly, exactly to suppress the immune system, as especially after transplantation). Now, a new study reports that rapamycin can actually enhance the immunological response to vaccination in aging humans: The most immediate caveat: simply showing the mounting of a better antibody response after short-term use of the drug is not the same thing as actually showing more effective defense against and clearance of the target pathogen after long-term use of the drug to slow the aging process. In (2), The latter study has been discussed in this thread on the CR Society Listserv; I should have, but haven't yet, responded to some of Tom's objections to the latter. References 1. Joan B. Mannick, Giuseppe Del Giudice, Maria Lattanzi, Nicholas M. Valiante, Jens Praestgaard, Baisong Huang, Michael A. Lonetto, Holden T. Maecker, John Kovarik, Simon Carson, David J. Glass, and Lloyd B. Klickstein mTOR inhibition improves immune function in the elderly Sci Transl Med 24 December 2014: Vol. 6, Issue 268, p. 268ra179 Sci. Transl. Med. DOI: 10.1126/scitranslmed.3009892 [No PMID yet] 2. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Goldberg EL, Romero-Aleshire MJ, Renkema KR, Ventevogel MS, Chew WM, Uhrlaub JL, Smithey MJ, Limesand KH, Sempowski GD, Brooks HL, Nikolich-Žugich J. Aging Cell. 2014 Nov 26. doi: 10.1111/acel.12280. [Epub ahead of print] PMID:25424641[PubMed - as supplied by publisher] Free Article