DAVID T. NASH, MD
About three generations ago, most physicians learned very little about cholesterol during their medical school and in-hospital training, other than the history of very early work by a Russian researcher feeding cholesterol to rabbits, creating an atherosclerotic-like lesion. Many practicing physicians one generation ago doubted the value of treating elevated levels, and lay publications criticized attention to such minutia. Six decades of double blind controlled trials have converted cholesterol to a daily conversation piece, and into the standard of care requirement for almost all individuals with known cardiovascular diseases and many asymptomatic individuals with elevated risk factors. A few nihilists still dramatically proclaim that treating cholesterol is a “con game,” and others publish a variety of alarmist articles citing infrequent side effects of statin drugs, including violent behavior. Still others declare authoritatively that “there is no evidence that lowering your cholesterol level will lengthen your life.” However, most experienced clinicians recognize the important role of lipids in atherosclerosis and the importance of secondary prevention in those with proven vascular disease.
We are faced today with a global increase in aging populations, significantly impacting the already large number of associated risk factors and illnesses whose treatment threatens to overburden a strained worldwide healthcare system. Unfortunately, aging has not been examined with an appropriately intense effort, and has been treated with lip service or diligent neglect until recently. There is a direct analogy—aging is now the new cholesterol. Physicians must shorten the decades of nihilism which slowed the development of appropriate measures to deal with cholesterol, and understand more about aging.
DEMOGRAPHICS OF AGING
The percentage of the U.S. population aged over 65 years is projected to increase from 12% in 2000 to approximately 20% in 2030 with the total number expected to increase from 35 million to 75 million. Worldwide the number of persons aged 65 years or older was estimated to be 420 million, and by 2030 the number approaches one billion. In 1995, the proportion of the population over 65 years in Florida was 19%, the largest in the nation. By 2025, the proportion of Florida residents over the age of 65 years is projected to be 26%.
The aging of the world population is the result of several factors, among them the declines in fertility and increases in life expectancy in developed nations. This gain contributed about 30 years of life expectancy to those living in Western Europe, the United States, Canada, and perhaps larger gains in Japan and Italy—exceeding any similar period in recorded history. But life expectancy improvements over the last 165 years did not occur with uniform reductions in all-age mortality. In contrast to the gains made by the elderly today, nearly a century ago it was increases in infant and childhood survival that contributed largely to the increase in life expectancy. Much of the improvement has also come with increased control of infectious disease, and subsequent scientific advances in the treatment of older persons. Although it is not possible to predict the future, it appears likely that rises in life expectancy will continue to occur.
Exceptional longevity can be considered as living to 100 years and it is rare, with a prevalence of approximately 1 in 10,000 individuals in the general population. This longevity could be due to a delay in or escape from age-related diseases such as cardiovascular disease and cancer, which may be related to the ability to age slowly. Genetic factors may play an important role in this ability, since relatives of long-lived individuals often are more likely to enjoy longevity as well. Aging is a complex process that has shown to be linked to accumulation of DNA damage.
Another change in the way people are aging involves the transition from dying from infectious diseases or acute illnesses to an increase in living with chronic illnesses and degenerative diseases. However, studies of health trends come with caveats since health is a multidimensional notion and no single indicator will suffice to capture all changes and trends. What we can do is study the development of disease risk factors, indicators of morbidity, and functional limitations—all of which have a potential impact on an individual’s quality of life over a period of time.
Tied into that is disability, an important factor when it comes to assessing aging and the costs involved. Usually, it is measured by a set of self-reported limitations, using various severity markers. The activities of daily living (ADL) measurement demonstrates dependence on others for feeding, dressing, transferring, bathing, and continence. Surprisingly, evidence has shown that disability prevalence is falling even as age increases. Most evidence for people younger than 85 suggests a postponement of disabilities, particularly those due to cardiovascular disease.
An encouraging study found that 30 to 40% of a contemporary group of nonagenarians (individuals in their 90s) were independent from age 92- 100 years, suggesting that this ratio may persist beyond 100 years. A study of 32 U.S. super-centenarians aged 110-119 years noted that about 40% required little assistance or were independent, suggesting little worsening in the decade between the groups. Evidence also suggests that disability can be postponed through healthier lifestyles. The leveling off in disability level at these very old ages suggests that healthcare costs do not uniformly rise in the 10th and 11th decades of life. Indeed, the expected cumulative lifetime health expenditures for individuals in good health at age 70 were about the same or even a little lower than expenditures for less healthy people, despite the greater longevity of healthier elderly people.
Interestingly, the conclusion of these studies is that very long lives are not the distant privilege of some future generations, nor a far off financial burden. Furthermore, very long lives are a probable destiny of many individuals currently alive in developed nations. Nonetheless, the projected growth in the elderly support ratio, (i.e. the number of persons aged > 65 years per 100 persons aged 20-64) is a concern. If the number of working taxpayers relative to the number of older persons declines, as it likely will, fewer adults will be available to provide personal care to the elderly, and to perform all the physically demanding jobs of a growing industrial society. Less public financial resources to pay the costs of caring for the elderly will be available. It is vital to begin to understand the process of aging itself, and recent research findings provide important insights. An important new factor in the study of aging is the role of telomeres.
TELOMERES AS A MOLECULAR CLOCK
Telomeres are the chromatin structures at the ends of chromosomes, protecting them from wear much in the same way the plastic casing on the ends of shoelaces keeps them from fraying, and are important for maintaining chromosome integrity. Their shortening due to incomplete replication functions as a molecular clock, counting the number of cell divisions, and ultimately resulting in cell cycle arrest and cellular aging. Interestingly, telomere shortening can be slowed by the enzyme telomerase, which is able to extend shortened telomeres. However, the only cells in our bodies that show enough telomerase activity to slow wear and produce cellular immortality are embryonic and germ cells. In sharp contrast to the life promoting qualities above, telomerase also is activated in cancer cells and directly enables unlimited growth and malignant traits. The close connection of telomere biology to aging and cancer makes it an important subject worthy of study and further research. Identifying mechanisms underlying variation in adult longevity permits some insight into the evolution of life history and variations in aging. Telomere length shortening in humans is emerging as a biological marker since such shortening is associated with aging-related diseases and early mortality.
A genetic study of Ashkenazi Jewish centenarians utilized 38 subjects and a similar number of their offspring and offspring matched controls, measuring inheritance and maintenance of telomere length as well as variations in two major genes associated with telomerase enzyme activity. The study revealed that centenarians and their offspring maintain longer telomeres compared to controls with advancing age, and that longer telomeres are associated with protection from age-related disease, better cognitive function, and lipid profiles of healthy aging.
Telomere length was also studied in 38 sex-and-aged matched (aged 97- 108) centenarians in good health versus poor health. Healthy centenarians with physical function in the independent range and the absence of hypertension, congestive heart failure, heart attack, dementia, cancer, stroke, or diabetes, were compared to centenarians with physical function limitations and 2 or more of these conditions. Healthy centenarians had significantly longer telomeres than their unhealthy counterparts.
Short telomere length has also been linked to cardiovascular disease morbidity and mortality. A sample of 236 Caucasian randomly selected subjects from the MacArthur Health Aging Study (aged 70-79) were assayed for telomere length of white blood cells at the start of the study and 2.5 years later, with changes in length carefully measured. For women, short baseline length was associated with greater mortality, for men, telomere length shortening after 2.5 years, was associated with greater mortality. Telomere length may represent an important prognostic factor for longevity if these findings are confirmed by future controlled studies.
Telomere shortening represents a cell-intrinsic mechanism leading to DNA damage accumulation and activation of DNA damage checkpoints in aging cells. Activation of these DNA damage checkpoints in response to telomere dysfunction results in induction of cell senescence, a tumor suppressor mechanism protecting cells from genomic instability. Consequently individuals are more susceptible to various diseases and an increase in cancer risk as they age.
Telomeres may also have an additional role in the area of chronic illnesses. There is a great deal of variability in the susceptibility, age at onset, and progression of cardiovascular disease. Although traditional cardiovascular disease risk factors such as elevated cholesterol and hypertension play an important and much heralded role; differences in biological aging may provide an additional clue to the incomplete solution that presently established risk factors provide. Telomere length at birth is determined in part by genetic factors, and is influenced by environmental factors including oxidative stress. Telomeres are known to be shortened in patients with coronary heart disease and heart failure. This may provide new avenues for research and development of future preventive and therapeutic strategies.
CHOLESTEROL AND GENETICS
Though they seem to be an indicator, non-lifestyle factors that affect aging and health don’t end with telomeres. Cholesterol Ester Transfer Protein (CTP) is an important regulator that manages the size of cholesterol particles in the blood and thereby influences the hardening of the arteries. Some individuals are born with a gene which causes a reduction in CEPT and less control of cholesterol size. This results in a higher level of HDL-C—the larger, low density cholesterol which is protective in terms of the progression of both atherosclerosis (hardening of the arteries) as well as memory loss and Alzheimer’s Disease. The Ashkenazi Jews who are centenarians tend to have higher levels of HDL then aged matched controls. Drugs are currently in development to lower CEPT, but proof of the benefits is still not determined with certainty.
Since genetic factors impact both telomere length and mortality, attempts have been advanced to understand their impact rather than direct biological effects. Twins make the perfect subjects for such a study because they are genetically identical. A study of Swedish twins analyzed telomeres within each pair. Length was measured and the twins with the shortest telomeres had a 3X greater risk of death during the follow up period than their co-twins with the longer telomere length. The authors suggest that telomere length predicts survival independent of genetic influences.
Telomere length is influenced by more than genetics, and can be negatively impacted by certain treatments. Cancer therapy’s success depends markedly on the high replication rate of cancer cells, which is frequently observed in higher grades of malignancy. However, this same characteristic is present with many of the normal regenerative tissues of the body, and this accounts for some of the toxicity of cancer therapy. In response to cell killing by chemotherapeutic agents, normal regenerative tissues replicate faster and this may result in accelerated telomere wear leaving telomeres shorter than before therapy. Newer chemotherapeutic agents may provide treatments which minimized this effect.
MEASURES TO IMPROVE TELOMERE LENGTH
While a way to safely and easily increase telomere length will appear to be a fools’ errand, along the lines of the Spanish explorer Ponce De León and his travails in Florida, there are some interesting clues to future therapeutic efforts. To investigate if age and telomere length are related to habitual exercise, investigators studied VO (2) max, which is an individual’s aerobic exercise capacity and an indicator of physical fitness. Young (18 to 32 years) and older (55 to 72 years) adults were studied, using inactive and endurance trained health adults of both genders. VO (2) max was found to be the only independent predictor of telomere length in the overall group. Also, those in the older group who perform vigorous aerobic exercise were able to maintain that capacity as they aged to a surprising extent. Exercise is clearly a key practice when it comes to slowing telomere shortening and redefining age, yet data shows that fewer than half the population participates in it regularly.
THE DHA STORY
There is another alternative, one which presents an easy compliance aspect to lowering the rate of telomere shortening. Since dietary intake of marine omega-3 fatty acids is associated with an improved survival in coronary heart disease, a group of investigators examined blood levels of 3 omega fatty acids to determine the rate of telomere shortening in patients with coronary artery disease. Over 600 ambulatory patients with stable coronary artery disease were recruited for the Heart and Soul study and were followed for 6 years.
The authors measured telomere length in white blood cells at the start and 5 years later. Those individuals falling in the lowest 25% of omega 3 fatty acids DHA and EPA in the body experienced the fastest rate of telomere shortening, while those in the highest quarter demonstrated the slowest rate. With each standard increase in the omega 3 fatty acids, a 32% reduction in the odds of telomere shortening was seen.
THE NIH BOMB-SHELL
Few if any conditions are as frightening to individuals and as associated with aging as Alzheimer’s. A recent review of more than 250 studies carried out by the National Institute of Health (NIH) produced by dozens of experts meeting in late April 2010 has concluded that no significant evidence exists for any drug or behavioral change in terms of improving cognition or delaying the onset of Alzheimer’s disease. The national media had a simple response—“Nothing Works.” This sort of therapeutic nihilism is unjustified. The NIH group did not review aging. The analogy to the early years of minimal cholesterol treatment are striking, and a new set of publications is sure to follow.
While the future is not easily predicted, it is clear that an aggressive national effort directed at this aging tsunami will become increasingly necessary. About two generations ago physicians began the process of testing whether reducing elevated cholesterol levels would benefit patients at risk for coronary heart disease. While there many physicians with a nihilistic attitude toward cholesterol at that time and even today, a large number of double blind placebo controlled trials of statin drugs have demonstrated the value of this approach. The so-called lipid hypothesis is essentially established. It is likely that there will be a similar lag between clinical trials showing effective anti-aging approaches to therapy and the adoption of evidenced-based guidelines for the preventive care of the aging.
There is little doubt that future studies will significantly impact the effects of an aging global population with a variety of behavioral, pharmacologic, and perhaps genetic approaches to therapy. Physicians and other scientists have begun the process of acquiring the information and planning new controlled trials to establish the basis of a future therapeutic approach. There is an old world saying, “You are not required to complete the task at hand, neither are you free from making a start.” This saying is even truer today.
ABOUT THE AUTHOR
David T. Nash, M.D., may be reached at Syracuse Preventive Cardiology, 600 East Genesee Street, Syracuse, NY 13202; or Email: firstname.lastname@example.org.