Aging: An Amazing Continuous Process

William Shakespeare, in "As You Like It," famously dissects the seven ages of man, wherein man returns to infancy in his seventh age:

"Last scene of all,

That ends this strange eventful history,

Is second childishness and mere oblivion,

Sans teeth, sans eyes, sans taste, sans everything."

I am not a Shakespearean scholar, but these words have stayed with me since my freshman college English course 60 years ago. Perhaps this is the reason I have been collecting books on the subject of aging, books I recently reviewed while conducting research for this article. It appears that as I have gotten older, I subconsciously have been searching for ways to slow down the aging process and to delay the inevitable. (Fortunately, I am not yet acting like a child, have teeth, can see and have an enormous appetite.)

In a New York Times editorial, William Safire wrote, "Nothing makes the weak strong or the fearful brave as much as the body's innate drive to stay alive."¹ The inevitability of aging and the specter of dying always have haunted human life, and the desire to overcome aging has long been a human dream-one that I recently have espoused. Today, the topic of aging is timely and fashionable, as America has become an increasingly "gray" nation with people over 85 comprising the fastest-growing segment of the population. People are living longer, but 150,000 people also die each day worldwide-that is nearly two per second-and about two-thirds of that number die from aging or diseases brought on by aging.²

It may be obvious that aging brings a host of infirmities and many of us will spend our last days residing in a nursing home. This article briefly discusses the definition of aging, what it means to age, the process itself, why we age and anti-aging methods designed to increase longevity.

Definition

Aging defies an easy definition, at least in biological terms. It is not merely the passage of time. Age is the manifestation of biological events that occur over a span of time. Age in years does not directly correlate with biological age; it includes characteristics such as health, cognitive function and disability rates.³ Biological aging has been fully and not simplistically defined as the universal, progressive and deleterious process of escalating loss of molecular fidelity with age, resulting stochastically from the intrinsic metabolic processes of the organism, which degrades its ability to maintain homeostasis in the face of environmental stressors, leading to increased intrinsic vulnerability to pathology and mortality.⁴

The Aging Process

Usual aging involves two sets of problems. First, many organs and structures, including the bones, kidneys, heart and lungs, gradually lose strength. Second, immune, endocrine and reproductive functions also decline. These changes place the elderly at risk for disease and dysfunction, especially when major stressors occur.

The second set of problems of typical aging relates to the build-up of high levels of blood fats and sugar and subsequent hypertension.⁵ All major organ systems are affected. There is little doubt that the incidence of cardiovascular disease increases exponentially with age. It is the leading cause of death in older age groups in all industrialized nations. Atherosclerosis, a thickening and hardening of the walls of the arteries, is responsible for most deaths.

The immune system is exceedingly complex and consists of hundreds of vital components that change with aging. As a result, older people are less efficient in mounting an immune response when required. Some gerontologists believe the increased incidence of cancer with age is the result of an immune system less capable of detecting and destroying cancer cells.⁶

Like the immune system, the endocrine system affects all the body's cells. Hormonal changes with age reduce the physiological reserve in tissues and organs. The secretion of many hormones, including testosterone, insulin, androgens and thyroid and growth hormones, decreases with normal aging.

There is general agreement that the weight of the brain decreases from young adulthood to old age. The number of cells lost may not, of itself, be significant unless the loss involves cells whose vital functions cannot be assumed by others. Alzheimer's, a disease characterized by a mass of fibers found in the brain cells, usually is an affliction of older people.⁷

The male and female reproductive systems are also affected by aging. Compared to the conspicuous (menopausal) reproductive aging that occurs in women, the senescence of the male reproductive system is a more gradual affair. Additionally, the skeletal system is affected through loss of bone. Such loss begins in the 50s for both sexes, but then proceeds more rapidly in women than in men.⁸ Women suffer more bone loss than men because they experience dramatic drops in estrogen production due to menopause. Women also start with a lower bone density than their male counterparts and lose bone mass more quickly as they age.

Why We Age

There are many theories as to why we age. Some focus on the accumulation of errors in the genetic code, while others invoke loss of telomeres (telomeres are the repeated sequences found at the end of chromosomes that shorten with repeated cell divisions). Loss of telomeres results in depletion of somatic cells that normally are replaced when they die and depletion of stem cell pools essential for healing and maintenance of tissues. Anthony Cerami, PhD, advanced the glycation theory of aging in 1985. It postulates that reactions between proteins and sugars in the body eventually form a class of compounds called advanced glycation end products that can damage other proteins as well as DNA and RNA. These end products foster abnormal bonds between adjacent protein strands, a change called cross-linking. Cross-linked proteins account for wrinkling and sagging skin, arteriosclerosis and development of neurodegenerative diseases.⁹

Other changes occur as well. Mutations in chromosomes can cause cancer, and mutations in mitochondria (the organelles within the cell that that convert amino acids, fatty acids and sugars into energy and affect the production of adenosine triphosphate (ATP)) reduce energy and cause dysfunctions in vital organs. Both are the result of problems caused by free radicals. Extracellular aggregates including beta amyloid and transthyretin, and possibly other substances, interfere with normal cell metabolism. Intracellular aggregates such as lipofuscin also can build up, interfering with normal cell metabolism. Cellular senescence is another cause of aging.¹⁰

Anti-Aging Methods

There are manufacturers of nutritional products that advertise their antioxidant formulations as a means to retard aging. These compounds (vitamins E and C, butylated hydroxytoluene) are said to work by combating the effects of free radicals and delaying the decay of mitochondria. None has been proven safe and effective. However, resveratrol, found naturally in the skin of red grapes, is a promising candidate that may help prevent and treat diseases associated with aging. Resveratrol can accelerate the production of SIRT1, an enzyme that has proven beneficial for both treating and preventing cancer, cardiac disease and Alzheimer's.¹¹ SIRT1 belongs to a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases termed sirtuins. These proteins can extend lifespan in model organisms (i.e., fruit flies, nematode worms) and are important in mediating the anti-aging effects of a low-calorie diet.¹² Whether such proteins can have anti-aging properties in human subjects is an interesting and still open question.

Experiments going back to the 1930s have shown that feeding laboratory animals about a third fewer calories than they would eat freely, without causing malnutrition, can dramatically increase their longevity.¹³ This is not simply because such animals tend to overeat when given the chance and become obese; animals that eat sensibly and maintain a constant body weight throughout their lives still live shorter lives than those given less food.¹⁴

Other researchers working with the nematode worm Caenorhabditis elegans discovered a mutation of a single gene that added at least 50% to the youthful adult life span.¹⁵ Recently, scientists have combined mutants in two pathways well known for life-span extension and reported a five-fold expansion of longevity in the same nematode species.¹⁶ Many other mutants have been discovered-not only in nematodes but also in fruit flies and mice. The mutations confer a delay in aging at most equal to that achievable by simply restricting calorie intake. This work was an immense breakthrough because it proves that single genes can be modified in a test tube and then introduced into human patients by gene therapy. Somatic gene therapy is still in a preliminary stage but there is widespread confidence that it eventually will work.¹⁷

While a cure for aging may be a long way off or may never occur, we do know that morbidity and mortality are significantly affected by lifestyle. Men and women ages 45 to 79 who are physically active, eat plenty of fruits and vegetables, do not smoke and consume alcohol moderately have, on average, one-quarter the risk of death during a given year than people with unhealthy habits.¹⁸

Final Thoughts

There is recent evidence that not all species weaken and become more likely to die as they age. Tortoises actually get stronger and less likely to die as they get older due, in part, to their large size--larger animals live longer than small ones--and their protective armor. One giant tortoise lived to be 255 years of age. Longer life spans also provide an evolutionary advantage for reproduction. Giant tortoises have an average life span of more than 100 years. Research on the hydra, a freshwater polyp, shows that it constantly renews body tissue and thus may escape cell senescence and its consequent aging effects altogether.¹⁹ Many people had thought that aging was inevitable and occurred in all organisms as it does in humans. However, increasing weakness with age is not a law of nature, and there clearly is a need for more research before scientists fully understand the evolutionary causes of aging and become better able to address them.²⁰

References

1. Safire W. "Why die?" New York Times, 1 January 2000: 31.
2. DeGray A, Rae M. Ending Aging. New York, NY: St. Martins Griffin; 2007.
3. Hayflick L. How and Why We Age. New York, NY: Ballantine Books; 1994.
4. Op cit 2.
5. Rowe JW, Kahn RL. Successful Aging. New York, NY: Pantheon Books; 1998.
6. Weil A. Healthy Aging. New York, NY: Alfred A. Knopf; 2005.
7. Gomes A. "Aging genes: the sirtuin story unravels." Science. 2011;334(6060):1194-1198.
8. Op cit 3.
9. Op cit 6.
10. Op cit 2.
11. Guarente L. Sirtuins, "aging and medicine." New Engl J Med. 2011;364(23):2235-2244.
12. McCay CM et al. "The effect of retarded growth upon the length of life span and upon the ultimate body size." J Nutrition. 1935;10:63-79.
13. Ibid.
14. Op cit 2.
15. Friedman DB, Johnson TE. "A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility." Genetics. 1988;118(1):75-86.
16. Pankaj K et al. "Germline signaling mediates the synergistically prolonged longevity by double mutations in daf-2 and rsks-1 in C. elegans." Cell Reports. December 2013.
17. Op cit 2.
18. Lieberman D. The Story of the Human Body: Evolution, Health and Disease. New York, NY: Pantheon Books; 2013
19. Martinez DE. "Mortality patterns suggest lack of senescence in the hydra." Experimental Gerontology. 1998; 33(3):217-225.20  
20. Jones OR et al. "Diversity of ageing across the tree of life." Nature. 2013; doi: 10.1038/nature12789. Published online 8 December 2013. Accessed 24 January 2014.

About the Author

Max Sherman is head of Sherman Consulting Services in Warsaw, IN. He can be reached at [email protected].

Cite as: Sherman M. "Aging--An Amazing Continuous Process." Regulatory Focus. February 2014. Regulatory Affairs Professionals Society.