Aging

DEFINITION OF AGING

Aging is a syndrome of changes that are deleterious, progressive, universal and thus far irreversible. Aging damage occurs to molecules (DNA, proteins, lipids), to cells and to organs. Diseases of old age (diseases which increase in frequency with age, such as arthritis, osteoporosis, heart disease, cancer, Alzheimer's Disease, etc.) are often distinguished from aging per se. But even if the aging process is distinct from the diseases of aging, it is nonetheless true that the damage associated with the aging process increases the probability that diseases of old age will occur.

Some gerontologists prefer to use the word senescence because "aging" implies that the passage of time necessarily results in deterioration (biological entropy) — which is certainly not true during the early, developmental, time of life (before the age of 10 or 12 in humans). I will retain the word "aging" because I believe the association between aging & deterioration is universal as adult years progress and because the distinction between aging & development is very strongly established in conventional language. Also, shorter words make for slightly faster reading.

AGING: CAUSE & CURE

What causes aging? In other words, what lies behind the progressive deterioration that accompanies the passage of time after maturity — with special interest to humans. To answer in outline form:

* METABOLIC DAMAGE

o FREE RADICALS

o GLYCATION

* CELLULAR SENESCENCE & DEATH

o TELOMERE SHORTENING

o DECLINING & INADEQUATE DNA REPAIR & AUTOPHAGY

o DECLINING & INADEQUATE ANTI-OXIDANT DEFENSE

o DEFECTIVE CELL CYCLE CONTROL, PROTEASOMES, LYSOSOMES & HEAT SHOCK PROTEINS

* TOXIC & NON-TOXIC GARBAGE ACCUMULATION

o PROTEIN CROSS-LINKING & AGGREGATION

o ADVANCED GLYCATION END-PRODUCTS (AGEs)

o ATHEROSCLEROTIC AND AMYLOID PLAQUES

o INFLAMMATORY CYTOKINES

o LIPOFUSCIN

o CORTISOL

o METALS

o DDT, PCBs, etc

An organism that can create fewer free-radicals in generating energy (more efficient mitochondria), use less energy to live, have more effective antioxidant defenses, have better DNA protection, have better DNA repair, have a better immune system and detoxify more effectively in the liver — can reduce damage from endogenous & exogenous sources.

Glucose is necessary for energy production, but glucose causes glycation of proteins. Energy creation results in free radicals as a toxic byproduct. Toxic & non-toxic garbage accumulation is primarily a problem for non-dividing cells (like neurons & muscle cells) which cannot dilute-away the garbage. The damage which causes aging is the damage due to necessary metabolism. This damage affects DNA repair, antioxidant production, telomere length, cell-cycle control, proteosome function, etc. — resulting in reduced capacity to cope with increasing levels of damage.

Telomere shortening contributes to mortality only in a few tissues. Neurons & muscle cells are non-dividing and are thus not affected by telomere shortening. Telomere shortening may contribute to mortality most significantly for immune system cells & arterial epithelial cells. Even if telomere shortening in the immune system is proven to cause the majority of deaths in the very elderly, the mortality is better described as "failure of the weakest link" (like the death of wild horses from worn-down teeth) than as aging. If biological gerontologists are successful in finding means to greatly increase human lifespan, then telomere shortening in proliferative tissues may become far more relevant to human aging. (For non-dividing cells, notably neurons, metabolic damage & garbage accumulation could be considered the "weakest link" if it weren't for the fact that cell death is so different from cell senescence.)

Metabolic damage would be much less of a problem if its byproducts (cross-links, AGEs, lipofuscin, etc.) could be eliminated — along with whatever toxins (lead, cadmium, DDT, PCBs, etc.) manage to enter the organism. The so-called immortality of germ cells, bacteria and Hydra is probably due to the diluting-away of toxins (all of the Hydra cells are dividing cells). Lobsters — which have been proposed as candidates for negligible senescence — discard tissue by molting and appear to continue growing without ever maturing. Lobsters express telomerase in all organ tissues and may avoid senescence by the same mechanism as Hydra.

Why does CRAN (Caloric Restriction with Adequate Nutrition) extend lifespan? The most plausible explanation is that the lower level of calorie utilization & energy production allows for lower levels of blood glucose (less glycation) and less free radical production. Efforts to duplicate CRAN with a pill or genetic manipulation probably have no chance of success.

If the "accelerated aging" diseases are a guide, damage to DNA — mitochondrial (mtDNA) and nuclear (nDNA) — are the damage that is most central to aging. Damage to nDNA and nDNA repair capability would be the worst because mitochondria (and mtDNA) can be replaced by lysosome recycling. But the source of that nDNA damage would still be mitochondria. Defective nDNA repair along with associated cell senescence & apoptosis leads more to aging, whereas the nDNA damage itself leads more to cancer. For mtDNA damage, the damage becomes most serious when the lysosomes are no longer capable of removing defective mitochondria which are producing high levels of free radicals. Free radicals are the primary cause of the nDNA and mtDNA damage in the first place. Defective mitochondria play a central role in accelerated apoptosis, leading to tissue degradation. If defective mitochondria which produce high levels of free radicals are the major source of aging damage, then the most effective step towards slowing aging would be improving lysosomal function by providing more efficient enzymes to the lysosomes.

The maximum lifespan of one or a few individuals of a species is taken as a proxy for the rate of aging of that species and for the idea that only extensions of maximum lifespan are relevant to slow aging. But most people die of aging-related diseases: cardiovascular disease, cancer, Alzheimer's Disease, etc. The damaging aging processes that increase vulnerability to these diseases are more relevant to vast majority of people than influences on maximum lifespan. For this reason it is not misleading to speak of diabetes, tobacco, dietary AGEs, ultraviolet radiation and other exogenous sources of tissue damage as accelerating aging — especially when the damage so closely resembles the tissue damage normally associated with aging. For the vast majority of people good genes can only reduce (not prevent) the aging effects of damaging exogenous agents.

The "mechanisms of aging" tend to be quite tissue-specific. Replicative senescence leads to aging of T cells and blood vessel endothelial cells, whereas other forms of cell senescence leads to aging of stem cells in the pancreas and selected areas of the brain. Non-mitotic cells such as neurons and myocytes are more vulnerable to oxidative stress and DNA damage. Glycation leads to cross-linking of extracellular proteins. For any particular individual, the combination of heredity and environmental conditions will cause some tissues and organ systems to age (or experience damage) more than others — and becoming the "weakest link" leading to mortality. The number or individuals who do not succumb to age-related death specific to a particular tissue or organ is a tiny minority.

Until molecular repair technologies are available, good health practices, supplements and organ transplantation are our best hope of bridging the time between now and the Age of Negligible Senescence.

Effects of Aging

Because the digestive system has a lot of reserve built into it, aging has relatively little effect on its function compared to its effects on other organ systems. Nonetheless, aging is a factor in several digestive system disorders. In particular, older adults are more likely to develop diverticulosis and to experience digestive tract disorders (for example, constipation) as a side effect of taking certain drugs.

Esophagus: With age, the strength of esophageal contractions and the tension in the upper esophageal sphincter decrease, but the movement of food is not impaired by these changes. However, many older adults are likely to be affected by diseases that interfere with esophageal contractions.

Stomach: With age, the stomach lining's capacity to resist damage decreases, which in turn may increase the risk of peptic ulcer disease, especially in people who use aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Also with age, the stomach cannot accommodate as much food (because of decreased elasticity), and the rate at which the stomach empties food into the small intestine decreases, but these changes generally do not produce any noticeable symptoms. Aging has little effect on the secretion of stomach juices such as acid and pepsin, but conditions that decrease acid secretion, such as atrophic gastritis, become more common.

Small Intestine: Aging has only minor effects on the structure of the small intestine, so movement of contents through the small intestine and absorption of most nutrients do not change much. However, lactase levels decrease, leading to intolerance of dairy products by many older adults (lactose intolerance). Excessive growth of certain bacteria (bacterial overgrowth) becomes more common with age and can lead to pain, bloating and weight loss. Bacterial overgrowth may also lead to decreased absorption of certain nutrients, such as folic acid, iron, and calcium.

Pancreas, Liver, and Gallbladder: With age, the pancreas decreases in overall weight, and some tissue is replaced by scarring (fibrosis). However, these changes do not decrease the ability of the pancreas to produce digestive enzymes and sodium bicarbonate. As the liver and gallbladder age, a number of structural and microscopic changes occur.

Large Intestine and Rectum: The large intestine does not undergo much change with age. The rectum does enlarge somewhat. Constipation becomes more common. This may be due partly to a slight slowing in the movement of contents through the large intestine and a modest decrease in the contractions of the rectum when filled with stool.