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Aging/Comorbidities/Immunity/Early Aging Senescence....HCV liver disease
 
 
  Jules Levin, NATAP
 
I love how some researchers insist on debating the science of aging & senescence - is it true, does it occur? they ask - meanwhile thousands of older HIV+ suffer with early onset of frailty, gait problems, and numerous comorbidities: heart disease both clinical & subclinical - 50% of antidepressants, bone disease, cognitive & neurologic impairment - all with earlier onset in HIV & occurring more often. Here are studies I selected ALL on the NATAP website I have accumulated over the years BUT I had to select these because there are so many more on the website & although this seems like a lot there are many more & I tried to not overwhelm too much so I picked only some. BY THE WAY you won't see HCV related liver disease discussed much BUT WE KNOW HIV/HCV coinfected progress much more quickly, develop advanced disease more quickly & are more susceptible therefore to liver disease, HCV-related liver cancer and end-stage liver disease & death ALL because of the impaired immune system in HIV+, accelerated aging?
 
Accelerated Longitudinal Gait Speed Decline in HIV-Infected Older Men. (MACS)......."The 57% increased hazard of developing slowed gait holds significant implications for the care of those aging with HIV+ who may be at increased risk of lower extremity limitations, hospitalization, and death. Accordingly, efforts to prevent and treat mobility loss in those aging with HIV should be a major public health focus. Given recent evidence from the general population, promoting physical activity and a healthy lifestyle are the best current options41.".......we analyzed gait speed measurements collected over a 6-year period in the Multicenter AIDS Cohort Study (MACS), an ongoing study of the history of HIV infection that includes HIV+ and HIV- men who have sex with men (MSM)......The current study demonstrates a statistically significant difference in the trajectory of gait speed decline between men aging with HIV and demographically similar HIV- men......"The capacity to walk independently is a central component of independent living and essential to maintaining quality of life. To our knowledge, this study is the first to evaluate age-related gait speed decline prospectively in a large HIV+ population and compare these observations to a demographically similar HIV population......http://www.natap.org/2015/HIV/062415_01.htm
 
Risk of Melanoma in People with HIV/AIDS in the Pre- and Post-HAART Eras: A Systematic Review and Meta-Analysis of Cohort Studies.....http://www.natap.org/2014/HIV/042514_01.htm....."The increased risk of melanoma in populations with HIV/AIDS may be related to effects of HIV infection on the immune system although these are complex, including not only immunodeficiency, but also chronic immune activation and inflammation, and immune dysfunction and senescence......Immunosuppression is known to be associated with melanoma, shown by the increased risk of organ transplant recipients treated with immunosuppressive drugs [1].
 
Inflammation Is Associated with Endothelial Dysfunction Among Individuals with Treated and Suppressed HIV Infection.....http://www.natap.org/2010/CROI/croi_67.htm......levels of inflammation were more predictive of worsened endothelial function than traditional risk factors in individuals with HIV..... These findings suggest that even treated and suppressed HIV-infected individuals may be at increased risk for cardiovascular disease, and that chronic inflammation in the setting of treated HIV disease underlies the higher rates of atherosclerosis in this patient population. Our findings also argue for an independent role of direct drug toxicity in driving early cardiovascular disease"
 
Our results suggest that HIV-1 infection induces an accelerated aging of T lymphocytes, which is associated with the clinical progression to AIDS and death.......http://www.natap.org/2009/HIV/011309_01.htm.......during HIV-1 infection, accelerated aging of T cells, or immunosenescence, may occur due to the continuous highly productive viral replication, which persistently stimulates immune cells
 
Viro-Immunologic Abnormalities in Gut Associated Lymphoid Tissue Caused by Acute HIV Infection are not Reverted by Early Initiation of HAART.......http://www.natap.org/2009/CROI/croi_135.htm....Early HAART introduction does not contain the establishment of HIV infection in GALT. A less efficient clearance of intracellular HIV DNA is associated with the persistence of immunological impairment in GALT as reflected by the skewed expression of cytokines in this reservoir.......Six months of HAART resulted in a sustained decrease of intracellular DNA in PBMCs (mean decrease of 0.85 ± 0.15 log10 cp/106 cells, p= .0002, Tab. 1), with patients 1, 5 and 6 presenting the smallest decrease (Fig. 2A).....In contrast to these results, intracellular HIV DNA in RSC lymphoid tissues was only partially reduced (mean HIV DNA levels: 1 log10 cp/μg; mean decrease 0.50 ± 0.20 log10 cp/μg, p= .04; Fig. 2B, Tab. 1). Moreover, when comparing the rate of reduction of HIV DNA in these two reservoirs, a trend to a less efficient clearance of HIV intracellular DNA was observed in RSC (p= .07).....This study shows that the GI muscosa is a unique site of HIV infection which behaves differently compared to other reservoirs during PHI, as demonstrated by the lack of efficient clearing of intracellular HIV DNA levels, despite early introduction of antiretroviral therapy. A lesser control over infection may account for the poor immunological profile in the GI tract compared to peripheral reservoirs. Prevention of mucosal assault by means of alternative therapeutic strategies may represent the turning point in the treatment of acute HIV infection and optimize the use of HAART in this key phase of HIV disease.
 
Physical Exercise Prevents Cellular Senescence in Circulating Leukocytes and in the Vessel Wall.....Middle-aged marathoners and triathletes who had been training for decades had significantly less telomere erosion than their more sedentary counterparts .......http://www.natap.org/2009/HIV/120109_03.htm
 
Fish Oil Slows Telomere Aging.....http://www.natap.org/2010/HIV/012010_01.htm
 
A Low CD4/CD8 Ratio During Effective ART Predicts Immunosenescence and Morbidity/Mortality......"each 10% decrease in the CD4/CD8 ratio was associated with 48% higher odds of serious non-AIDS events (P=0.045) and 13% higher odds of mortality (P=0.01)......subjects with low CD4/CD8 ratio during effective ART exhibit heightened T cell activation & senescence, while those with normal ratios showed levels closer to normality.....".......http://www.natap.org/2014/CROI/croi_178.htm ....'EARLY ART MAY HELP'
 
Viro-Immunologic Abnormalities in Gut Associated Lymphoid Tissue Caused by Acute HIV Infection are not Reverted by Early Initiation of HAART
 
T cell Senescence and Proliferation Defects Persist in Treated HIV-infected Individuals Maintaining Viral Suppression and Are Associated with Poor CD4+ T Cell Recovery (Hunt et al).....http://www.natap.org/2010/CROI/croi_88.htm
 
T Cell Activation and Senescence Predict Subclinical Carotid Artery Disease in HIV-Infected Women......http://www.natap.org/2010/HIV/011111_01.htm...... http://www.natap.org/2010/CROI/croi_35.htm.........Compared with HIV-uninfected women, HIV-infected women had markedly higher levels of CD4+ and CD8+ T cell activation (P < .01) (Table 1 and Figure 2). These differences remained significant when we restricted the HIV-infected group to those who were treated with HAART and had achieved viral suppression......In adjusted models, among HIV-infected women, the prevalence of carotid lesions was directly associated with the percentage of CD4+ and CD8+ T cells expressing activation markers........In comparison with HIV-uninfected controls, the percentage of CD8+ T cells with an immunosenescent phenotype (CD28-CD57+) was increased among the HIV-infected women (P < .01) (Table 1 and Figure 2). This difference persisted even among HIV-infected women who were receiving HAART and who had undetectable HIV RNA levels......
 
Immunosenescence and HIV (Deeks et al) ......Accelerated immunosenescence in the setting of HIV disease is associated with increased morbidity and mortality, prompting the need for more investigation into its causes, diagnosis, and treatment.......http://www.natap.org/2012/HIV/062512_02.htm
 
Premature immunosenescence in HIV-infected patients on highly active antiretroviral therapy with low-level CD4 T cell repopulation.....http://www.natap.org/2010/HIV/062310_02.htm......The present study shows that patients with a low-level CD4 T cell repopulation have a lower level of naive CD4 T cells and -TREC levels, and also a trend to have lower thymic volume. In addition, higher activation levels and CD57 expression in naive CD4 T cells (senescence marker) could be involved in the enhanced cellular apoptosis, directly affecting the total CD4 T cell pool......We propose that the deficit in naive CD4 T cell production causes a compensatory proliferation of peripheral cells, which may accelerate their senescence. In a parallel way, higher cell activation may also contribute to the premature senescence of CD4 T cells. For example, T cell immunosenescence has been described in rheumatoid arthritis and in HIV-infected donors without treatment, similar to that observed in elderly individuals, and it is probable that this premature immunosenescence occurs due to compensatory proliferation by a deficiency in the ability to generate a sufficient naive CD4 T cell count.47,48 Premature ageing of naive CD4 T cells could be a risk factor for developing a proliferative inability and also a higher CD4 T cell apoptosis rate. Thus, CD4 T cell sequestration in lymphoid tissues induced by activation along with apoptosis may determine a lower CD4 T cell repopulation in these patients. This poor CD4 T cell repopulation probably favours the inability of T cell immunity to effectively suppress thymotropic virus, playing an important role in both thymic activity and peripheral T cell homeostasis, as thymocytes and naive CD4 T cells preferentially express the CXCR4 co-receptor.
 
HIV induces astrocyte [brain] senescence and is reversed by -catenin induction.....http://www.natap.org/2015/CROI/croi_145.htm
 
Is HIV a Model of Accelerated or Accentuated Aging? YES.....http://www.natap.org/2015/HIV/060115_01.htm
 
Immune Senescence, Activation and Abnormal T cell Homeostasis Despite Effective HAART, A Hallmark of Early Aging in HIV Disease.....http://www.natap.org/2009/CROI/croi_130.htm.....Immune activation drives T cell turnover and senescence in HIV-1 infected and uninfected aging individuals as indicated by significantly higher levels of activation (expression of CD38+HLADR+) on both CD4+ and CD8+ T cells of HIV-1 infected and uninfected aging individuals compared to young uninfected subjects. Impact of HAART Initiation on Immune Regulation (activation/senescence) in Aging HIV-infected Women -Women's Interagency HIV Study.....http://www.natap.org/2012/CROI/croi_72.htm
 
Role of CD8 T Cell Replicative Senescence in Human Aging and in HIV-mediated Immunosenescence - Review (Effros)......http://www.natap.org/2012/HIV/020712_01.htm.....HIV infection is generally believed to be causing "accelerated immunosenescence," due in large part to effects from chronic immune activation and inflammation......Chronic HIV disease, even when controlled through antiretroviral therapy (ART), is associated with accelerated immunosenescence, as evidenced by the higher numbers of senescent memory CD8 T cells and increased inflammatory milieu. Interestingly, even in HIV disease, a high proportion of late-differentiated, putatively senescent, memory CD8 T cells are specific for CMV antigens. As in age-related immunosenescence, these HIV-associated changes result in dysregulated immunity, chronic diseases linked to inflammatory damage, and increased morbidity and mortality. .......
 
Premature Aging and Immune Senescence in HIV-1-Infected Children.....http://www.natap.org/2015/CROI/croi_146.htm......"The proportion of CD8+ cells with a senescent phenotype (CD28-CD57+) was higher in HIV+ children.......HIV-1-infected children had a lower telomere length compared to age- and gender- matched controls, suggesting an accelerated biological aging; - age-adjusted telomere length is shorter in ART-untreated than in ART-treated children, thus suggesting that HIV-1 itself, rather than exposure to antiretroviral drugs, influences the senescence process"
 
Detectable Viral Load Aggravates Immunosenescence Features of CD8 T-Cell Subsets in Vertically HIV-Infected Children......http://www.natap.org/2012/HIV/082312_02.htm......"These results indicate that as described in adults,7 HIV infection induces a premature ageing of the effector CD8 pool. The presence of senescence markers was increased in aviremic children when compared with healthy children, as consequence to the HIV exposition from birth. However, the frequency of all CD8 subsets studied is preserved in this aviremic group and level of senescence was significantly lower than in children with uncontrolled viral load. These data clearly indicate that the control of viral load can reduce dramatically the premature ageing in the CD8 T-cell population."
 
Quality-Of-Life Predicts Survival in HIV: HIV & aging......."In summary, physical HRQL (health-related quality of life) predicts survival in the long term in a population of HIV-infected patients receiving HAART independent of demographic and clinical variables.....Of patients with a PHS, 26 (20%) died in quartile 1 (indicating worst HRQL), 17 (13%) died in quartile 2, 10 (8%) died in quartile 3, and 5 (4%) died in quartile 4 (indicating best HRQL) ( p<.001)....investigators found that poorer health-related quality of life in the following areas were associated with an increased risk of death: physical functioning (p < 0.001), pain (p < 0.001), role functioning (p < 0.001), social functioning (p = 0.01), and general health (p = 0.01).......http://www.natap.org/2010/HIV/011710_01.htm
 
Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations......http://www.natap.org/2011/HIV/062711_06.htm
 
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