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Immunosenescence & Aging in HIV
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'perhaps the greatest concern among patients and certainly that older patients face. Of the approximately 1 million people with HIV in the USA about 20% are over 50 yrs old, a significant percent are between 40-50, and its estimated that by 2015 50% will be over 50 yrs old.' What follows is an exchange of discussion by experts in this area of HIV and Aging on immunosenescence and the increased and early onset of comorbidities we are seeing in HIV today. Jules Levin
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Age at Cancer Diagnosis Among Persons With AIDS in the United States
Meredith S. Shiels, PhD, MHS; Ruth M. Pfeiffer, PhD; and Eric A. Engels, MD, MPH
From the National Cancer Institute, National Institutes of Health, Rockville, Maryland.
HIV and Premature Aging: A Field Still in Its Infancy - Editorial: "Age at Cancer Diagnosis Among Persons With AIDS in the United States" (pdf of published study attached) - (10/06/10)
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......we need to do interventions to test the hypothesis......we cant ignore CMV as a culprit driving T cell senescnce. The senescent T cells can produce the inflammatory mediators reponsible for CVD metabolic and bone disease. In the end its not about definitions but what can we do to reverse the co morbidities we see.
Alan Landay
Rush University Medical Center
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There is nothing unique about HIV-1 in that regard. Indeed, the accumulation of senescent T cells (mostly CD8+) during chronological aging is associated with another virus (i.e., CMV) that establishes latency and causes chronic stimulation, clonal expansion, and eventual senescence of CD8+ T cells. So it's the long term exposure to viral antigens-- be it CMV or HIV-- that is ultimately causing the problem. Even in ART-treated HIV-infected persons, there can still be ongoing exposure to viral antigens, since the virus is still present in the body.
In terms of possible other aspects of aging that are associated with HIV disease, senescent T cells may also play a role. For example, our cell culture data shows that senescent T cells secrete multiple pro-infammatory cytokines ( e.g., TNFa, IL-6) as well as RANKL-- all these cytokines that stimulate increased maturation and activaton of osteoclasts, the cells that resorb bone. And there is clear evidence of bone loss reports in HIV-infected persons before the era of ART, so bone changes cannot be blamed on the medications,, but rather, may actually relate to T cell-mediated inflammation. In studies that are unrelated to HIV/AIDS, it has been shown that senescent T cells accumulate in many forms of cancer, putatively due to chronic stimulation with tumor antigens. Thus, many pathologies normally seen in older individuals are accelerated in HIV disease, and may ultimately relate to T cell senescence, as Seema has written.
Rita Effros, PhD
Professor of Pathology and Laboratory Medicine
David Geffen School of Medicine at UCLA
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The early occurrence of T cell senescence (immune senescence) and correlation to activation and inflammation is established. This early T cell senescence in HIV infected is similar to that seen in ageing individuals. The real question is "Does early immune senescence co-relate/cause early co-morbidities" and is focus of our ongoing studies. That if corrected for the risks can it be defined "accelerated ageing" is based on how one would define normal ageing. Different factors responsible, are well elaborated below.
Activation of the immune system results in release of mediators of inflammation and these mediators can impact the immune system as well as the organ system, based on all available studies. Our efforts are to unfold causes and consequences of early co-morbidities in HIV infected and each of the published study/review contributes towards understanding it.
Seema Desai PhD
Assistant Professor
Department of Immunology/Microbiology & Medicine
Rush University Medical Center
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Great conversation! I'll throw in a couple of points that my group tends to consider when we discuss aging. I'm sorry this is long and I don't know if this actually helps at all, but here goes:
1. I was a participant in a conference a number of years ago at Hopkins jointly sponsored by the JHU Center on Aging and NIA: the major point of discussion was whether "frailty" actually existed or was it a consequence of building up diseases; the second most hotly contested issue was whether "normal aging" existed, or whether it was the consequence of the buildup of disease such as atherosclerosis (physiological disease), nuclear DNA damage (cellular disease), etc; so, even among those who have dedicated their lives to studying "aging" there is no clear consensus on what it means....
2. Having said that, there are clearly processes that occur at the cellular level (Doug Wallace showed us mitochondrial aspects), physiological level (e.g., loss of renal function, dementia), and organismic level (e.g., gait problems) that most people would say are at least associated with the length of time someone has lived, if not "aging"; interestingly, however, they don't always go in parallel. In other words, some people "age" more quickly in some aspects than others. Some of these differences seem connected to genes, some to particular exposures (q: does smoking "age" your lungs more quickly or simply "damage" them?), and there will be some of course that are G x E interactions.
3. So, even if we accept a term like "normal aging", we should consider the differences among people in decline in different organ systems. In HIV, one system clearly recapitulates time-dependent degradation: the immune system. We consider two aspects of that: increased innate activity (inflammation) and decreased adaptive activity (immunosenescence). The elderly slowly but surely have increased inflammation, and slowly but surely become immunosenescent. One question raised by Dr. Volberding is whether it's important HOW one comes to that state. In the time-dependent version, immunosenescence is probably driven by things like loss of T cell progenitor cells, buildup of nuclear DNA damage, loss of ATP generation due to somatic mtDNA damage, etc; in HIV it's driven by virus-mediated cell death. In a similar manner, the increased inflammation comes about in somewhat different ways.
4. So, clearly, HIV is not simply some form of magically accelerated "normal" aging, whereby, for example, the gradual decline in T cell progenitors that normally takes decades and is driven by exposures to a wide variety of immunogens (although variable from person-to-person for the reasons discussed above), somehow occurs in years or possibly even months. Or the gradual decline in mtDNA-mediated ATP generation somehow happens in a very short period of time.
5. But you DO have a rapid buildup of inflammation in HIV, and a rapid immunosenescence none the less. We believe that a pro-inflammatory melieu accelerates the pathophysiology in most chronic diseases, so one would anticipate seeing earlier incidence of clinical diagnoses such as coronary heart disease, T2DM, dementia, COPD, CKD, all of which are associated with older age if the inflammation isn't present (unless a person has a powerfully predisposing genetic or environmental issue at play). In this sense one could ask: is being an obese Pima Indian "accelerated aging"? The increased adiposity yields high inflammatory status, in turn yielding increased incidence at earlier ages of heart disease, diabetes, etc. In fact, if a person has an accelerated form of any organ-specific disease, whether genetic or environmental (declining pulmonary function, renal function, liver function, vascular function, etc), might the resultant inflammation be considered as contributory to "accelerated aging"? At least some researchers in each of these fields thinks so, since I have heard each of these described as "accelerated aging" in recent meetings. And we now know that these conditions impact each: humans are integrated organisms where each organ and tissue affects all others organs and tissues; e.g., Cystatin C levels not only predict continued loss of renal function, they predict heart attacks. Systemic inflammation, from any cause, accelerates chronic disease processes.
6. Finally, in HIV you have one additional feature that you don't have in these other settings of chronic inflammation that at least some consider "accelerated aging": chronic loss of adaptive immune function. This state lends some credence to the notion of increased incidence of conditions that require immune surveillance such as infections and some cancers. So, in my mind, I would be amazed if there weren't increased incidence at earlier ages of virtually all chronic diseases associated with aging, either because of the increased inflammation that's present, or the variably deficient adaptive immunity, or both. This includes cancer. Biologically, it doesn't make any sense to me that there wouldn't be.
So, given this analysis, should HIV be branded "accelerated aging"? In one sense, no: different mechanisms at the biochemical and cellular level. In another sense, yes: similar outcomes at the organ, organism and disease levels. In addition, there is the political issue: is it a good thing for the people with HIV, their health care providers, and the needed research for this "branding" to continue? In this regard I would argue yes, but I'm sure there are those that would disagree:
1. Some clinical interventions that are useful in the elderly may be important to those with HIV and vice-versa;
2. While the differences at the root causes need to be understood, the similarities at the higher organizational levels (organs, tissues) should yield important insights into both how HIV causes diseases, and what goes on with aging. I view the recent disagreements about cancer incidence as an example of the good that can come from this kind of branding: at the end of the day we WILL know the truth, and the truth about cancer in HIV is critically important. Would we have been so quick to move on this issue without this concept of HIV as accelerated aging? I'm not sure, but one could argue probably not.
3. What I'm calling "branding" can be an important organizational tool for funding and research, improving focus and giving a framework that becomes understood to reviewers, collaborators, etc. allowing rapid communication of ideas, and enabling creative thinking.
4. However, as always, there are dangers: a lack of understanding of the differences can cause unnecessary, lengthy and wasteful arguments; badly designed research; and inappropriate funding that removes resources from truly necessary research. So a clear exposition of what we mean by this concept should be brought forward.
Just a few thoughts, and if you read this far, thanks!
Russell Tracy
University of Vermont
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why we should focus on mechanisms is that doing so will allow us to identify targets for effective interventions.
To be sure, learning about shared mechanisms will have an even greater impact on health in general as interventions targeting these pathways will have relevance not just to the HIV-infected population, but also to everyone else...
And this is why our current system of funding biomedical research (based on organ system) makes less and less sense. Inter-institute collaborations in funding will need to become more common to support the multidisciplinary research required to address these issues.
Peter Hunt
UCSF
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"I'm not suggesting that immune senescence isn't happening....we should insist on data not just observational findings...... If
senescence explains aging, how many aspects of aging should be
accelerated (after age-adjustment of the population) and how many of the
organ system problems are due to direct or indirect issues of HIV
infection of the organ in question."
Paul Volberding, MD
Professor and Vice Chair, UCSF Department of Medicine
Chief, Medical Service SF Veterans Affairs Medical Center
Co-Director, UCSF-GIVI Center for AIDS Research
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from Jules: I agree, we need to sort out contributing factors. There appears to be many contributing factors including accelerated immune senescence and many others including viral reservoirs, concomittant chronic diseases, poor diet/exercise/unhealthy lifestyle etc. In the meantime we don't have much time to lose, many HIV+ individuals are over 50 and over 60 already and do not have time to wait for study results that take many years. They need interventions and a better understanding of what is going on. So we need to try and find a way to reverse senescence. Some suggest starting HAART earlier would help to improve the early onset of senescence and it may be that starting HAART earlier may have a beneficial affect, it may help, whether it totally reverses it is in question, a study would be useful. But again earlier HAART does not help the 250,000+ HIV-infected now who are over 50, and the 500,000+ expected in 2015.
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