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Aging Before Your Time?

By Richard J. Havlik, M.D., M.P.H. and Donna M. Kaminski

Fall 2009


Introduction

We are all aging, whether we are HIV positive or negative. It is part of the natural course of life. A small number of individuals live to 100 years of age with minimal disease and disability. Others seem to have accelerated aging with deterioration of multiple body systems, disability, and chronic diseases. Naturally, this brings us to wonder what factors account for this difference in aging.

To date, we've been able to identify a couple of factors. Resveratrol, a compound found to help fruit flies and yeast live longer, has been studied for its role in slowing down the aging process. Other studies have also looked at a gene called FOXO3A. People who have mutations in this gene seem to have a slower aging process. Studies are under way to see if these factors could be modified to help slow down the aging process, and to see what else seems to affect aging.


An Aging Epidemic

Fortunately for people with HIV, treatment has improved and people are living longer. It's estimated that by the year 2015, almost half of people with HIV will be over 50. In New York City, over 36% are over 50. By 2005, the number of people with AIDS in the U.S. who were over 50 was seven times higher than it was in 1990. Some of this may be due to greater testing efforts, but some of it is also due to improved access to HIV treatment.

But older adults are still getting diagnosed later in their disease than younger people. An Italian study looked at 1,977 people who received care from 1986 to 1998. About a third had a late diagnosis of AIDS, and the most significant factor linked with that late diagnosis was age. People who were over 45 were more likely to be diagnosed at a later stage of HIV disease.

One study found that only 59% of HIV-positive adults over 65 survived more than three years, compared with 90% of adults aged 20 to 39.
Another study found that more than half of newly diagnosed older adults developed AIDS in less than a year. A third study found that only 59% of HIV-positive adults over 65 survived more than three years, compared with 90% of adults aged 20 to 39. Despite earlier testing efforts and greater access to medications, people are getting diagnosed at later ages and are at risk of shorter survival times.

In order to support people over 50, we need to have a better understanding of aging and HIV. This article will review what is known about the aging process and what is seen in people with HIV. Finally, it will review what needs to be better defined, and what might slow aging regardless of HIV status.


Common Manifestations of Aging

Aging is not a disease but a collection of changes in various body systems that occur as we age. These changes might be quite evident, such as graying hair, or may be subtle and detected only when an organ system is stressed. These changes should be separated from specific diseases, such as diabetes, which become more frequent with age. This is difficult to do, because there is usually an interaction between aging systems and diseases. Another important principle is that different body parts or systems age or wear out at different rates in different people.

The Immune System: The thymus gland, located in the upper chest, produces CD4 and other immune cells. These cells fight infections either directly or by signaling B cells to produce antibodies. Shortly after birth, the thymus gland begins to shrink, and production of such cells is reduced. The total number of cells decreases as we age and they function less efficiently. This results in more infections in some older individuals.

Aging Before Your Time?CD4 cells are the first line of the body's defense against infections. In older adults, new CD4 and CD8 cells are created more slowly. The number of B cells is also reduced, so fewer antibodies are produced. These changes lead to immunosenescence, a general weakening of the immune system.

Skin and Body Shape: As we age, the skin thins in the arms, legs, and face due to loss of fat under the skin, making it more vulnerable to injury. In addition, excessive sun exposure or lifelong smoking can lead to wrinkles and more frequent skin cancers. Also, there is a redistribution of fat to the organs in the belly area in men and to a certain extent also in women. Generally weight increases until well into middle age, but can then begin to decrease overall, along with the poor distribution of fat in the body.

Eyes and Ears: It is quite common for changes in the lens of the eye, such as cataracts, to occur with aging. In many cases this results in the need to use glasses for close work. Generally, there is a loss in the ability to hear higher tones, especially in a crowded room. Environmental noise over a lifetime can worsen this condition.

Muscle: Volume and strength of muscles are reduced with aging. Runners and other athletes do not compete as well against younger athletes because of this and other issues that affect fitness. Increasing disuse of muscles and reduced physical activity, however, can also contribute to muscle loss.

Bone: Bone loses its density, accelerating over time, particularly in women after menopause, and its strength is reduced. This situation can lead to more frequent broken bones or fractures. This loss also occurs in men at older ages.

Liver: The detoxification function is maintained with age because liver cells can continue multiplying even at older ages, but with less efficiency than they do at younger ages. For example, the size of the liver can be reduced as we get older, and overall function can be challenged as we age. Liver function can also be impaired by drugs and excessive alcohol.

Kidneys: The cleaning function of the kidneys operates effectively until older ages, when clearing of waste products decreases. Among the many factors that affect kidney function are protein in the diet and other conditions such as high blood pressure and diabetes.

Lungs: The capacity of the lungs decreases with age, but this usually does not present a problem, unless factors like smoking have had a major impact.

Heart and Blood Vessels: The major blood vessels thicken due to fibers in the tissue of arteries solidifying and losing their elasticity. This is different from atherosclerosis, which results in hardening of the coronary arteries. The thickening of major arteries forces the heart to work harder to maintain its output. This can often result in enlargement of the heart muscle, sometime leading to heart failure after many years.

Blood Pressure: The thickening of the major arteries can also lead to the systolic blood pressure (the top number when recording blood pressure) becoming elevated. This can have a gender-specific effect in people over 55. For example, men have a higher risk of high blood pressure until age 45 than do women. From 45 to 54, men and women have an equal risk, and after 55 women have a greater risk. If untreated, this can increase cardiovascular risk and lead to a stroke.

Blood Fats (Lipids): Cholesterol, especially the low-density lipoprotein (LDL) type or "bad" cholesterol, tends to increase with age. This may also be caused by a lifelong fatty diet or bad genes or a combination of these factors. Diabetes and low levels of thyroid hormone can also be associated with higher levels of cholesterol and triglycerides.

Blood Sugar (Glucose): At older ages, the insulin needed to control glucose levels is not as well regulated and sugar levels tend to rise. Sometimes this leads to diabetes. This problem is often only revealed after a glucose test, taking a load of sugar by mouth, which can reveal poor regulation of glucose levels. Obesity, diet, and genetics can alter these relationships. Insulin resistance is common among individuals with later-onset diabetes, and is a central problem among our aging population.

Brain and Nerves: Aging can worsen mental function, when combined with other factors. Simple memory lapses, such as forgetting someone's name, are quite common at older ages but do not signal serious disease. Special testing may be necessary to detect subtle changes. Peripheral nerves (such as those in the hands and feet) monitor pain, touch, temperature and other sensations and there may be reductions in sensitivity with age, but generally external factors, such as trauma or disease, diminish sensation.

Why do these various systems fail with aging? There are three theories as to the cause of aging. The first is programmed cell death, where destructive factors are genetic and built into the DNA of our cells. The second theory suggests that the inevitable wear and tear of life on our body systems, including the destructive effects of byproducts from the oxygen we breathe, results in cell death, especially of the immune system. The third theory simply suggests that aging is a combination of known and unknown factors.


How Does HIV Affect Aging?

Among people over 50 with HIV we are seeing other conditions, commonly referred to as comorbidities. One study of 165 people with HIV over age 55 found that the most common comorbidities were high blood pressure (41%), chronic obstructive pulmonary disease (29%), and diabetes mellitus (22%). Softening of the bones (osteoporosis), cardiovascular disease, liver disease, and cancers like lymphoma and Kaposi's sarcoma have also been found to be more common. A key question is whether the virus itself or HIV treatment influences the aging process in a negative way. Here's a summary of the known possible effects of HIV on the body.

The Immune System: Of course, HIV damages the immune system by infecting and destroying the type of T cells known as CD4 cells. But it can also lead to a dysfunctional increase of certain T cell-related functions. This activation can have negative effects on the body, since inflammation, which usually helps to heal tissues, can get out of hand. The levels of cytokines, especially one called interleukin-6 (IL-6) may be increased to a level that adversely affects the body. In a long-term study of people with HIV, those with the highest IL-6 levels and high levels of markers known as C-reactive protein and D-dimer had a higher occurrence of cardiovascular disease and death.

One study showed that older adults were not seeing the same CD4 increases as younger people. It is thought that CD4 cells may not respond as robustly when HIV meds are started in people who are over 50.
People with HIV may also make less interleukin 2 (IL-2) and IL-2 receptors, causing CD4 cells not to work as well. This can cause the body to change the type of CD4 cells it makes, making fewer of the important "naive" cells that have never encountered an infection. Older adults with HIV have significantly fewer naïve CD4 cells than younger people with HIV. One study showed that older adults whose HIV meds were lowering the amount of virus in their body were not seeing the same CD4 increases as younger people. It is thought that CD4 cells may not respond as robustly when HIV meds are started in people who are over 50. And smaller numbers of CD4 cells were found in the gut of older people with HIV, suggesting that immunity is not as strong as we age.

Eyes and Ears: In the early years, eye problems due to opportunistic infections were relatively common. Now, such acute infections are rare, although there may be old scars that can affect vision. Hearing level is not known to be affected by the virus or treatment.

Bone: A metabolic complication of HIV infection is reduction of bone mineral density (BMD). In one study of people taking HIV treatment, BMD was reported to be low in 52% of people, and an additional 10% had actual osteoporosis, a bone disease leading to increased risk of fractures. What's interesting is that this effect doesn't seem to be affected by HIV treatment. One study found greater levels of osteopenia (which comes before osteoporosis) in people with HIV regardless of whether they were on HIV treatment. Older age was an important factor in these findings.

Studies in HIV-negative people have found a relationship between LDL cholesterol that has been distorted with too much oxygen and the production of a blood factor from T cells that destroys bone. If confirmed in people with HIV, this might be a partial explanation of their low BMD. Other risk factors, such as less physical activity, decreased intake of calcium and vitamin D, cigarette smoking, alcohol use, depression, cocaine and heroin use, and low testosterone levels are also seen in people with HIV.

Liver: Although HIV is found in liver cells, damage is more likely to be due to other liver infections or taking certain HIV medications. Both hepatitis B and hepatitis C are common among people with HIV. Viramune in women with higher CD4 count can cause liver problems, as can other antiretrovirals, such as Zerit, Viread, Emtriva, Epzicom, Sustiva, Reyataz, and Aptivus.

It has also been found that people with liver disease and HIV are more likely to have diabetes than those who are HIV negative. One study of people with HIV and hepatitis C who were on HIV meds found higher rates of diabetes. When this study looked back to see if this effect was seen before HIV combination therapy became standard practice, they found that it wasn't. Therefore, this effect may be further associated with HIV medications and their effects on several metabolic pathways.

Kidneys: HIV has been incriminated in a relatively rare but specific kidney disorder that can compromise kidney function over time. The condition, HIV-associated nephropathy, has been found to be more frequent in African-Americans with HIV and can lead to kidney failure in some cases. Viread can also lead to kidney problems in rare cases, and Crixivan must be taken with eight glasses of water a day to avoid kidney stones.

Lungs: Even after receiving HIV meds, people with HIV tend to be more vulnerable to pneumonia. This may be due to poor regulation of certain immune system proteins, especially the cytokine called TNFa (Tissue Necrosis Factor alpha) in the lung tissue. This deficiency is related to problems of immune function due to HIV infection. Also, studies have seen a reduction in the lung capacity of older men with HIV when performing a treadmill test. Although men could perform normal activities, the deficiency appeared when they were stressed with higher physical exertion. HIV-positive smokers seem to suffer more decline than HIV-negative smokers, suggesting some interaction of factors.

Heart: HIV does not have a direct effect on the heart muscle. But the blood vessels that feed the heart muscle may develop more atherosclerosis due to higher levels of virus and the inflammation seen in HIV disease. This is the conclusion of some experts based on the results of the SMART Study. This study compared two groups of people, one taking continuous HIV treatments and the other taking breaks based on their CD4 count. It was thought that breaks in treatment would minimize the rise in cardiovascular risk factors seen in people with HIV. But the study was stopped early because the continuously treated group did much better than the group that interrupted treatment. This led to current recommendations to avoid drug holidays to minimize cardiovascular risk.

Another theory has looked into whether the HIV meds may be causing an increase in heart attacks among people over 50. One study showed a 26% increase in heart attacks among people on HIV drugs. Another study showed that one year after patients started HIV treatment, they had higher rates of high blood pressure. It's important that HIV patients and their doctors be aware of heart comorbidities.

Blood Pressure: High blood pressure, or hypertension, in people with HIV is most likely due to factors other than HIV. These would include the standard risk factors of obesity, salt intake, African-American race, and physical inactivity. The grouping of hypertension with abnormal blood fats and high blood sugar may, however, be higher in persons with HIV.

Blood Fats (Lipids): A study in otherwise healthy HIV patients receiving HAART found that elevated cholesterol was more common than expected. It is possible that HIV treatment resulted in individuals returning to their pre-illness cholesterol levels because of weight gain or increased fat intake. Some of the protease inhibitors have been incriminated in increasing lipid levels more than others. The choice of drugs might be modified to avoid such increases.

Blood Sugar (Glucose): The protease inhibitors have been shown to increase problems of regulating glucose by affecting insulin functions. People on HIV meds may be more vulnerable to multiple cardiovascular risk factors. Physicians are aware of this potential and either manipulate the drug regimen or add glucose-altering drugs.

Brain and Nerves: AIDS dementia has become quite uncommon with current treatments. But recent studies have suggested that certain mental functions might be adversely affected by HIV or its treatment. These are known as HIV-associated neurocognitive disorders (HAND). One study compared 106 people living with HIV who were over 50 to 96 people with HIV aged 20 to 39. After adjusting for education, race, CD4 count, and viral load, the study found that people with HIV who were over 50 were three times more likely to have neurocognitive dementia than those under 40. Whether this finding is the result of the virus itself or inflammation has not been determined. Recent research has also suggested that there might be activation of biochemical products similar to those found in Alzheimer's disease. Fortunately, the abnormalities have been mild, but further research is necessary to understand the extent of such problems.

Another interesting finding is that there may be an association between HIV dementia and diabetes. In one study where over half of the patients were over 50, there was a link between dementia and diabetes among people with HIV. This effect wasn't seen among the patients over 50 who didn't also have HIV. (Other studies have suggested a relationship between abnormal glucose levels and dementia.)

Adverse effects on nerves in the hands and feet, called peripheral neuropathy, are quite common and can be debilitating. The symptoms vary from tingling in the legs to severe pain and difficulty walking. It is likely that HIV directly affects the nerves in the legs and spinal chord, although treatment with older HIV medications contributed to the problem. Treatment is mainly focused on minimizing the symptoms.


Does HIV Accelerate Aging?

It's not known whether the virus itself or the treatment might be speeding the aging process in some body systems or contributing to the onset of certain diseases.
The good news is that many people with HIV are living longer and better lives because of newer drugs. There is no doubt that mortality rates are down and life expectancy is increased. But whether the aging process is back to normal is still an open question. It's not known whether the virus itself or the treatment might be speeding the aging process in some body systems or contributing to the onset of certain diseases. The immune system is the most likely target because of the fundamental effect of the virus on CD4 cells.

Body shape changes mimic the changes that occur in older persons. The softening of bones is frequent, and cognitive changes are possible. In some cases a combination of factors results in extreme physical frailty. Still, the jury is out on whether overall aging is increased in people with HIV. Fortunately, this is now becoming an active research area.


What Can You Do?

There is a great deal that can be done to achieve a longer and better life, even for those who are older and HIV positive, based on a large body of research on risk factors in older persons. The obvious things that can be done are stopping smoking, avoiding mind-altering drugs, and maintaining only modest alcohol intake. The cardio-protective effects of aspirin and the positive effects of antidepressants may suggest that, when indicated, these can both be helpful in helping people with HIV to live healthier, longer lives. Control of cardiovascular risk factors, including lowering blood pressure or lipids if elevated and maintaining appropriate body weight, makes good sense. One should take advantage of appropriate cancer screening to promote early detection and treatment. Psychologically, depressive symptoms are common and need to be addressed.

Those taking HIV treatment need to maintain good adherence and be aware of the advances that are occurring. HIV meds with a minimal risk of increasing blood fats or glucose should be used to reduce cardiovascular risk. Such a strategy will go a long way to improve quality of life and increase longevity. As further research is completed, it is highly likely that more specific approaches will become available to assist the older person with HIV age more gracefully.

Richard Havlik is a medical epidemiologist, formerly with the National Institute on Aging.

Donna M. Kaminski is a fourth-year medical student and ACRIA's former Associate Director of Treatment Education.

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