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Delaying Aging for Men: Longevity Lessons from Women

ROBERT S. TAN AND MEENU JACOB

Case History

A 58-year-old college professor, who was considering retirement. He was happily married to his wife of 30 years, who currently was postmenopausal and on estrogens. He had heard that good preventive medicine could be one of the keys for life extension. He had had annual physicals since he was 45 years old and was generally well. He did not smoke but drank a glass of wine every night. He admitted to exercising infrequently. His main aim was to remain healthy through his “golden years,” and he was inquiring about possible interventions including diet, exercise, and hormones. He jokingly said that he wanted to live as long as his wife, who was 5 years younger than he. He requested to have blood drawn for evaluation. He realized that most of these tests would not be covered by insurance, but he wanted to proceed nonetheless. Physical examination revealed that he was 5 feet 7 inches, weighed 151 pounds, and had a body fat content of 23% and blood pressure (BP) of 120/85 mm Hg. He also had a mild degree of gynecomastia and normal testicular size. He did have some hair loss over his scalp and thinning of his skin, relative to his age. He was asked to catch a falling ruler with his fist to test his reflexes, and he did well on that test.

Significant laboratory results included: fasting glucose 96mg/dL, cholesterol 183mg/dL, triglyceride 180mg/dL, hemoglobin HbA_1C 5.1, insulin-like growth factor I (IGF-I; somatomedin C) 83ng/mL (range 90–360), total testosterone 273 ng/dL (range 260–1000), free testosterone 47.5pg/mL (range 50–210), prolactin 5ng/mL, dehydroepiandrosterone sulfate (DHEAS) 429 µg/dL (range 20–413), thyroid-stimulating hormone (TSH) 2.05 µIU/mL, free triiodothyronine (T₃) 3.2pg/mL (range 2.3–4.2), free thyroxine (T₄) 1.0ng/dL (range 0.8–1.8), luteinizing hormone (LH) 2.2mIU/mL, estradiol 8pg/mL (range 10–50), insulin 21 µU/mL (range <20), homocysteine 12.9 µmol/L (range 5.4–11.4), prostate-specific antigen (PSA) 0.4 ng/dL.

The results were discussed with him, as it was noted that he had marginally low free testosterone and IGF-I. He also had marginally high homocysteine levels. He inquired about hormone replacement with testosterone and human growth hormone. He also asked for intervention to bring his homocysteine levels down, which he had heard was a risk factor for cardiac disease. He inquired about whether he should change his diet and if exercise would alter some of his biomarkers.

An Overview of Aging

In the United States, average life expectancy at birth is ∼79 years for women and ∼72 years for men. The oldest person for whom reliable records exist was a woman who recently died in France at the age of 123. The odds of someone living this long are about one in 6 billion. From a practical point of view, we can consider a century as the average maximum of human life. We are not there yet, of course. At present, average life expectancy for those born after 1960 is ∼85 years.

Before learning about delaying aging, it is imperative that one understands the processes of aging and the limitations of human life expectancy. The process of aging is universal for all forms of life. It begins at birth, or arguably on conception. Since time began, men have tried to go against aging, and to search for immortality. In reality, at the microscopic level, the accumulation of the diverse deleterious changes produced by aging in cells and tissues progressively impair function and can eventually cause death. Aging, in general, can be attributed broadly to the following five categories:

Past efforts to increase ALE-B did not require an understanding of the biological processes of aging. Such knowledge will be necessary in the future to significantly increase ALE-B and MLS. This knowledge is also required to satisfactorily plan for the medical, economic, and social problems associated with advancing age. For instance, many developed countries are increasingly burdened by social problems and increasing taxation as the population pyramid changes from one with a larger base of young people to one with a larger base of older people.1

There are many theories that have been proposed to account for aging, and they should be used to the extent they are feasible. The difficulty of the science of delaying aging or anti-aging principles is that often these theories are built on animal models, and they may or may not apply to human beings. Overall, the previous measures evolved by societies to ensure adequate care for older individuals are rapidly becoming inadequate because of changes in lifestyle, the growing percentage of older people, declining fertility rates, and the diminishing size of the workforce to provide for the elderly. Measures are being advanced to help with this problem but they largely address the preventive level, where lifestyle changes can significantly impact longevity. Prospects are bright for further increases in the span of functional life and improvements in the quality of lives of older individuals.

Limits to Human Longevity

As mentioned previously, the human life span at this point is limited to ∼122 years and average life expectancy to 85 years in developed countries, although there is a predilection for longevity in women. However, demographic approaches to modeling and forecasting mortality are often based on the observation of short-term trends in death statistics and the assumption that future mortality will exhibit patterns similar to those of the recent past. This extrapolation method has led some demographers to conclude that ALE-B in the near future may reach 100 years.

Similar predictions follow from other demographic models that establish a hypothetical link between risk factor modification and changes in death rates. Risk factor modification would include attention to diet, smoking cessation, and exercise. These predictions are examined within the context of the observed mortality records and their biological plausibility assessed based on the current theories of aging. Results indicate that these demographic models lead to mortality schedules that do not follow from the observed mortality record and that are inconsistent with predictions of biologically based limits to longevity. Although there is probably not a genetic program for death, the biology of our species places inherent limits on human longevity. As a human race, we were not built to last forever, but attention to some lifestyle habits may increase our chances of reaching the biological limit for our life span.²

Sex Differential in Longevity

There is a sex differential in longevity, with women outliving men. There may be biogenetic, environmental, and psychosocial perspectives that may be responsible for this sex differential³:

• Wellness and preventive health are practiced more by women than by men, and may explain some of the discrepancies. Women are more apt to go for Pap smears, mammograms, and cholesterol and BP checks than men are apt to go for cholesterol and BP checks.

Over the years, there have been many theories put forth as to the longevity differential. Most of these theories have been based on the animal kingdom, but much can be learned. For instance, higher death rates among male animals have been linked to the more risky behaviors that males exhibit, including fighting each other over females. A Scottish study from the University of Stirling shows that male wild animals have more parasitic infections than do females at the time of death.4 The researchers studied parasites in all kinds of mammals and determined that males have significantly more infections. The researchers postulate that males are generally larger than females, thus providing larger targets for parasites and animals that carry them. Another reason may be testosterone, which can suppress the immune system, making the body more prone to infection. The accompanying editorial in Science states that the parasite explanation might apply to humans, too, because men are more susceptible to parasitic and infectious diseases than are women. The editorialists point out that men in the United States, the United Kingdom, and Japan are twice as vulnerable as women to parasite-induced death. And in Kazakhstan and Azerbaijan, where parasite-related death rates are high, men are more than four times more vulnerable than women.

In another theory, based on studying people who live 100 years, researchers conclude that menopause may be a major determinant of the life spans of both women and men. Women’s life span depends on the balance of two forces: the evolutionary drive to pass on one’s genes, and the need to stay healthy enough to rear as many children as possible. Menopause draws the line between the two. It protects older women from the risks of bearing children late in life, and lets them live long enough to take care of their children and grandchildren. It is interesting to note that most animals do not undergo menopause. It seems that menopause evolved in part as a response to the amount of time that the young remain dependent on adults to ensure their survival. Pilot whales, for example, suckle their young until the age of 14 years, and they, along with humans, are two of the few species that menstruate. The theory assumes that longevity is linked to a later menopause. Hence, there is the argument for hormone replacement therapy for postmenopausal women. This may extend perhaps to testosterone replacement in postandropausal men.

Interestingly, in their studies of centenarians, Perls and Fretts⁵ found that a surprising number of women who lived to be 100 or more gave birth in their 40s. These 100-year-old women were four times as likely to have given birth in their 40s as women born in the same year who died at age 73. A study of centenarians in Europe by the Max Planck Institute of Demography in Germany found the same relationship between longevity and fecundity. Factors that allow certain older women to bear children, including a slow rate of aging and decreased susceptibility to disease, improve a woman’s chances of living a long time. Extending that idea, it is possible that the driving force of human life span is maximizing the time during which woman can bear children. The age at which menopause eliminates the threat of female survival by ending further reproduction may therefore be the determinant of subsequent life span.

The menopause theory, however, does not fully explain why women live so much longer than men. In all developed countries and most undeveloped ones, women outlive men, sometimes by a margin of 10 years. The gender gap for the longevity differential is most pronounced in those who live 100 years or more. Among centenarians worldwide, women outnumber men nine to one. The mortality gap even varies during other stages of life. For example, between the ages of 15 and 24 years, men are four to five times more likely to die than women. This time frame coincides with the onset of puberty and an increase in reckless and violent behavior in males. Researchers sometimes refer to it as a “testosterone storm” as most deaths in this male group come from motor vehicle accidents, followed by homicide, suicide, cancer, and drowning. After the age of 24 years, the difference between male and female mortality narrows until late middle age. In the 55- to 64-year-old range, more men than women die, due mainly to heart disease, suicide, car accidents, and illnesses related to smoking and alcohol use. Heart disease kills 5 of every 1000 men in this age group.

The hypothesis that the Y chromosome may be a limiter to life span could be challenged. The longevity differential can be closed with lifestyle modification. Whether the average person drinks and smokes, on the one hand, or exercises and eats vegetables, on the other, subtracts 5 to 10 years from one’s life or adds 5 to 10 years to one’s life. But to live an additional 30 years requires the kind of genes that slow down aging and reduce susceptibility to conditions such as Alzheimer’s disease, stroke, heart disease, and cancer. Clues about what those genes are and how they work could come from studying those who survive 100 years or more. The New England Centenarian Study is the only scientific investigation of the oldest people performed in the United States.6 Centenarians are a tremendous resource for the discovery of genes responsible for aging and the ways in which aging occurs. Discovering these genes could lead to testing people and determining who might be disposed to accelerated aging via diseases such as Alzheimer’s, cancer, heart disease, and stroke. Such individuals might eventually be treated to extend the prospect of their living longer.

Although women can expect to live longer than men, the gap is closing. Death rates have begun to converge in the past 20 years. Some researchers attribute the convergence to women taking on the behaviors and stresses formerly considered the domain of men, including smoking, drinking, and working outside the home. Death rates from lung cancer have almost tripled in women in the past 20 years. On average, middle-aged female smokers live no longer than male smokers.

Mood and Longevity

It has been assumed that people with better moods end up living longer. Depressed individuals, especially men, are more likely to take their own lives. In a recent study, however, it was found that mildly depressed older women tend to live longer than those who are not depressed at all.⁷ The findings are contrary to most other studies on the link between depression and mortality.

The finding that women with mild depression live longer suggests a survival mechanism. The Duke study⁷ was based on a group that started with 2401 women and 1269 men, all older than 65. They were interviewed about their health at roughly 3-year intervals from 1986 to 1997 and were separated into three categories: depressed, mildly depressed, and not depressed. Of the women, 10.5% were considered mildly depressed. The women with mild depression were, on average, 60% were less likely than other women to die during any 3-year period. Researchers took into account age, chronic illness, and other factors in calculating the mortality rate.

Interestingly, the researchers found that depression had no influence on the mortality of men. This study may support a theory that says mild depression may allow people to cope more easily with their problems and remove themselves from dangerous or harmful situations.

Summary of Existing Theories

There are several theories that explain longevity in different species.⁸ Most, if not all, of the theories are derived from animal models. As such, it is important for the clinician not to go overboard in recommending a particular strategy for life extension based on theory alone. However, these theories should be used in conjunction with conventional medical practice, and that would include lowering cardiovascular and cerebrovascular risk factors including blood pressure and cholesterol levels. These simple measures can realistically increase the life span. There is a lot of hype about life extension, but the clinician should stress lifestyle changes, exercise, and nutrition. It is important not to give false hope to patients or to rely on the “pseudoscience” of some anti-aging products.⁹

It has been hypothesized that genes control longevity. In one such study, the frequencies of 80 human leukocyte antigen (HLA) phenotypes in 82 centenarians and 20 nonagenarians in Okinawa, Japan, were compared with those in other healthy adults in various age brackets.10 Subjects over age 90 had an extremely low frequency of HLA-DRw9 and an increased frequency of HLA-DR1. In this age group the corrected relative risk (for number of antigens) and the p value for HLA-DRw9 were 5.2 and .0001, respectively; those for HLA-DR1 were 13.3 and .0367, respectively. Because a high frequency of DRw9 and a low frequency of DR1 are associated with autoimmune or immune deficiency diseases, the genetic protection against these disorders may contribute to longevity. A review by Ivanova et al¹¹ suggested links with other alleles as well, and this is demonstrated in Table 2-1.

DNA Repair Capability

In 1963, Dr. Leslie Orgel of the Salk Institute suggested that because the “machinery for making protein in cells is so essential,… an error in that machinery could be catastrophic to human survival.” The body’s DNA is so vital that natural repair processes kick in when an error occurs. However, the body’s system is unable to do this all the time, and thus accumulation of these flawed molecules can cause disease and other age changes to occur. If the DNA repair process did not exist, scientists estimate that enough damage would accumulate in cells in 1 year to make them nonfunctional. Others believe that aging is caused by DNA damage through intrinsic mutations or other age-related nonmutational or epigenetic changes such as altered methylation.

In a laboratory experiment, Zahn12 demonstrated that the DNA repair capacities of young and old mice were indeed different (Fig. 2-1). Alkaline filter elution has been modified by a freeze-grinding step that allows the evaluation of the DNA status of whole tissue, including mouse tail cross sections, with only small additional artifacts. Four to seven different organs from individually coordinated female mice, rated as young as 2 to 3 months of age and as old as 24 to 27 months of age, have been used. Tissues of individual mice differ significantly in their DNA status. Alkali-labile sites are relatively rare and differ in amount in the different organs in the young. They show significant increases in the old, reaching the highest values in the brain and the heart. Proteinase K–dependent DNA–protein cross-links are not prominent, nor are they increased with age in some organs, except in the brain and the heart. DNA damage susceptibility was measured after application of 3.5 µM nitroquinoline-N-oxide to 15-mg fresh tissue pieces for 90 minutes. The susceptibility is large and varies in wide ranges in the different organs. Upon 3-hour postexposure incubation in full medium, all samples showed DNA repair; the young reach nearly complete repair in the lung, whereas repair in the old is generally significantly decreased. In old brain and heart it is even near zero. This together with high values in alkali-labile sites and DNA–protein cross–linking suggests that these two organs may act as pacemakers and play a role as prominent codeterminants for the life span of the species.

CLINICAL IMPLICATIONS

Some patients may be tempted to purchase and use nutraceuticals or cosmetics that claim to be able to restore vitality by “repairing DNA.” The clinician should tell the patient that although the theory sounds interesting, at least in fruit flies and mice, there is no evidence that these substances actually work in human beings.

Telomeres and Telomerase

Telomeres are bits of DNA on the ends of our chromosomes; the parallel would be the hard ends of shoelaces. Fig. 2-2 is a graphic representation of telomeres. Although they do not contain genes, telomeres are important for replication or duplication of the chromosomes during cell division.

Telomere length recently has been described as a marker of cellular aging. The originator of the theory is Olovnikov¹³ In 1973, he proposed that cells lose a small amount of DNA following each round of replication due to the inability of DNA polymerase to fully replicate chromosome ends (telomeres) and that eventually a critical deletion causes cell death. Telemetries are specialized DNA sequences located at the end of eukaryotic chromosomes. In humans, telomeres are composed of repeats of the sequence TTAGGG reiterated in tandem for up to 15 kilobases at birth. Telomeres are synthesized by telomerase, a ribonucleoprotein reverse transcriptase enzyme that maintains the lengths of chromosomes. Loss of telomeres can lead to DNA damage. This association of telomere shortening and senescence in vitro has been established. Cells that have been supplied with an exogenous source of telomerase maintain a youthful state and proliferate indefinitely.

Hormones such as estrogens are frequently prescribed for women in the postmenopausal state. The Women’s Health Initiative’s recently published study had raised some doubt about the use of an estrogen/progesterone combination.14 Increasingly, testosterone is prescribed for men as they age. Preventive and therapeutic interventions with hormones can indeed improve quality of life. Whether hormone replacement results in longevity is yet to be determined.

Free Radical Theory of Aging

Dr. R. Gerschman first introduced this theory of aging in 1954, and later Dr. Denham Harman of the University of Nebraska College of Medicine further developed this theory. Free radical is a term used to describe any molecule that differs from conventional molecules in that it possesses a free electron. This is a property that makes molecules react with other molecules in highly volatile and destructive ways. They can attack cell membranes, creating metabolic waste products, including substances known as lipofuscins. An excess of lipofuscins in the body is shown as darkening of the skin in certain areas, so-called aging spots. Lipofuscins, in turn, interfere with the cells’ ability to repair and reproduce themselves. They disturb DNA and RNA synthesis of protein, lower our energy levels, prevent the body from building muscle mass, and destroy cellular enzymes, which are needed for vital chemical processes. Substances that prevent the harmful affects of free radicals are called antioxidants. Natural antioxidants include vitamin C, E, and A. As shown in Fig. 2-3, lipid peroxidation and changes in status of antioxidant compounds such as glutathione and others could be measures of oxidative stress.

In the 1930s, researchers discovered that they could extend the life of rats by 33% if they limited them to a very low-calorie diet. Oxidative stress is a major factor in aging and cellular senescence. It has been theorized that dietary restriction without malnutrition protected rats and mice against oxidative stress, decreased oxidative damage, and decreased accumulation of oxidatively damaged proteins within the mitochondria. The animals lived longer, suffered fewer late-life diseases, and appeared more youthful, and their bodies’ biological aging processes were slowed.15 Since that time, scientists have produced similar life-extending results with many other creatures, ranging from fruit flies to fish.

Is caloric restriction per se responsible for the observed benefits, or is some other factor that is reduced when calories are restricted? Studies show that limiting fat, protein, or carbohydrate, without accompanying caloric reduction, does not seem to increase maximum life span. Nor does supplementation with extra antioxidants and multivitamins. Varying the types of fats, carbohydrates, and proteins ingested also had no effect. In fact, no other intervention except caloric restriction has yet been shown to slow aging.

At this point, it is unclear that human life spans can be increased with calorie restrictions. Humans live much longer than many other creatures, and thus such studies are difficult to do. Studies with primates provide some clues. Investigations on monkeys have been underway since 1987, and preliminary results suggest that caloric restriction increases both health and life span in primates. Biomarkers of aging, such as insulin levels, glucose levels, and blood pressure, have led researchers to conclude that monkeys eating less age more slowly. In most such studies, calories are restricted to 30 to 50% of what the animal would normally eat. Care is taken to see that enough vitamins, minerals, protein, and fat are ingested for the proper functioning of tissues. The participants of the Biosphere-2 experiment in Arizona were forced to eat a low-calorie diet for 2 years because their food production was less than projected. They experienced the same anti-aging trends in biomarkers as were found in the monkey experiments. Fig. 2-4 shows blood pressure changes in the Biosphere-2 participants on this diet.

Dr. Terror, introduced at the start of this chapter, requested to be on testosterone replacement therapy. He also inquired about growth hormone replacement therapy, but changed his mind after finding out the cost of the treatment. He wondered about the advertised growth hormone secretagogues, but was advised that they rarely work. Quite a bit of time was spent discussing diet and exercise with him. As he was fairly thin, strength-training exercises were suggested for him. He decided to join a gym and exercised 45 minutes three to five times a week. He increased protein intake, fresh vegetables, and fruits (potential antioxidants). He was prescribed testosterone gel 5mg/day. After 6 months, on a routine follow-up visit, he was very satisfied. Overall, he said, his mood is better, and he is sharper and more energetic. He said the program restored some of his lost years. Objectively, it was noticed that despite weighing the same at 150 pounds, his body fat was reduced to 19%, implying muscle growth. His skin was less dry, his libido better, and he thought that testosterone was the elixir of youth for him. He was advised that testosterone was only supplementary and that it was the combination of testosterone with exercise and the right nutrition that seemed to have made him feel five years younger.