Do humans have a central aging clock, a control program that paces the aging of all body systems? This almost transcendental question has been popping up since the dawn of science. We seem to be getting closer to the answer these days. And the answer is simple: Yes and No. Don't laugh just yet. On one hand, it appears that we do not have a specific central program whose sole purpose is to make us age. On the other hand, we definitely have a program of development, i.e. a program that makes a single cell (zygote) develop into a complex organism. Some of the mechanisms of this development program seem to lack an "off" switch, and continue to run after the organism's development has been completed. These mechanisms are essential during growth and sexual maturation, but they appear to have an array of late side-effects. In fact, these mechanisms become harmful in a mature organism because they act as if development were still in progress. The result is the acceleration of aging and age-related diseases. Thus, the central aging clock appears to be a by-product of the body's developmental program, which doesn't get turned off at maturity.
This seemingly strange view is the main premise of the neuroendocrine theory of aging. The term neuroendocrine means that the theory has to do with an interaction of the central nervous system and the endocrine system (endocrine system regulates body functions through hormones). The neuroendocrine theory of aging was proposed by a prominent Russian scientist and physician Vladimir Dilman in the fifties. In the decades since, considerable evidence has accumulated to support this idea as one of the mechanisms of aging.
Before we go any further, we need to explain the notion of homeostasis. Essentially, homeostasis is a proper balance of the organism's internal environment. To be able to function normally, the body needs its physiological parameters to be within a certain optimal range: the temperature should be about 37oC (98.6F), blood pressure about 120/80, blood sugar 70-120 mg/dl, and so forth. Homeostasis is a tendency of a system to maintain internal stability, which involves keeping dozens of physiological parameters within an optimal range. If homeostasis is disturbed, the system tries to restore it. The failure to do so may results in death.
The tricky part is that homeostasis in a newborn is different from that of a child and both are different from that of an adult. For instance, the average level of hemoglobin (a molecule that transports oxygen in the blood) in infant boys is about 11 mg/100 ml, in ten year old boys -- about 13 mg/100 ml and in adult men -- 15 mg/100 ml; the average blood pressure in ten year olds is about 100/60, and in young adults -- 120/80. On one hand, at every stage of development an organism has to maintain homeostasis appropriate for that stage. On the other hand, to be able to grow and mature, the organism has to change (i.e. shift its homeostasis) to finally reach the parameters appropriate for maturity.
That's exactly what the developmental program does -- it gradually shifts homeostasis, pushing the body to consume and expend more energy, increase in size, develop reproductive organs -- in other words, to grow and mature. The problem is that this continuous shift of homeostasis does not stop at maturity but continues throughout life span. However, after maturity, instead of making you grow (the growth of body size does have an off-switch), it makes you age and develop are-related diseases. In that sense, our developmental program acts as an aging clock in later life.
Why didn't we develop an off-switch for our developmental program to prevent it from causing accelerated aging later in life? Perhaps the existence of such an off-switch didn't give any advantage for the species' survival in nature. Whatever the reason, we seem to have an equivalent of a built-in central aging clock. Fortunately, biological clocks are not rigid, their pace can be altered. Some influences would speed up the central aging clock, and others would slow it down.
Before discussing what might help slow down the central clock, we have to explain some of its physiology. The "central computer" largely responsible for the body's homeostasis is the area of the brain called the hypothalamus. Hypothalamus constantly monitors dozens of internal parameters of the body. If some parameter moves out of its proper range, the hypothalamus sends a signal to the pituitary, which is a master gland of the endocrine system. You can say that if the hypothalamus is the board of directors of homeostasis, the pituitary is the CEO. The pituitary translates the signals from the hypothalamus into hormonal messages to peripheral endocrine glands, such as the thyroid or adrenals (you can think of them as front-line managers). In turn, peripheral endocrine glands use their own hormones to give instructions to the work force - your various organs and tissues. Usually, the instructions are to increase or decrease some physiological function.
Another important concept that we need to introduce is negative feedback (a.k.a. feedback inhibition). Let us consider an example. In the winter, the body needs to raise its metabolic rate to compensate for colder weather. The hypothalamus sends the appropriate signal to the pituitary, which sends a signal to the thyroid to secrete more thyroxin (the hormone that rises metabolic rate). The resulting rise of the thyroxin level is sensed by the hypothalamus, which then stops sending the initial signal. This is an example of negative feedback, which is essentially the ability of the system to discontinue initial stimulatory signal when the goal has been accomplished.
To recoup: here's the nature of the central clock in a nutshell. The body's development requires a gradual shift of homeostasis. The hypothalamus is the main driving force behind that shift. The neuroendocrine theory of aging proposes that the hypothalamus implements the body's development program (which later becomes the aging clock) by becoming less responsive to negative feedback.
Let us consider another example. In young girls, ovaries produce only small amounts of estrogens but enough to exert a negative feedback, i.e. to make the hypothalamus stop urging the production of more estrogens. With increasing age, however, the hypothalamus becomes less responsive to negative feedback, and stimulates the ovaries to produce more estrogens. This leads to the well-known rise of estrogen levels with development and, eventually, to sexual maturity. Similar shifts of homeostasis occur during development in all body systems. Unfortunately, after maturity, the responsiveness of the hypothalamus to negative feedback continues to decrease causing further homeostatic shifts which now have a negative role, contributing to aging and degenerative diseases.
So, how do these homeostatic shifts induced by the central aging clock cause aging and age-related diseases? Many interrelated mechanism seem to be involved in this process but reviewing them all is beyond the scope of this article. The most important ones include insulin excess and impaired carbohydrate tolerance (a.k.a. syndrome X), abnormal stress response and age-related depression.
Age-related insulin excess and impaired carbohydrate tolerance are homeostatic shifts that have to do with energy utilization. Insulin is a hormone secreted the pancreas. It is secreted in response to the rise in blood sugar (glucose) normally occurring after a meal, and promotes the transport of glucose, amino acids and fats into cells where they are either burnt as energy, stored, or used as structural materials. A typical scenario after a meal is the following: as food is digested and absorbed, the blood glucose rises which triggers the secretion of insulin; in an hour or so insulin brings blood glucose to its original level or even lower. With age, the ability of the muscle and some other tissues to take up glucose in response to insulin declines, and the amount of insulin secreted after a meal increases. The net effect is that after a meal we have higher blood glucose for a longer period of time and more circulating insulin in the bloodstream. There has been much controversy whether a decreased sensitivity of the muscle to insulin causes excessive insulin secretion or vice versa. According to the neuroendocrine theory of aging the central hypothalamic clock is a factors contributing to both. The mechanism by which the hypothalamus causes these shifts appears to be complex and involves changes in appetite regulation, altered release of growth hormone and others.
Excess insulin and impaired glucose tolerance raise the levels of cholesterol, LDL and triglycerides, promote cell damage (via glycation and cross-linking), cause sodium retention and numerous other disruptions. As a result, these metabolic shifts contribute to the development of most age-related diseases including cardiovascular disease, hypertension, diabetes, obesity, cancer and impaired immunity.
The most common example of extreme glucose intolerance is noninsulin dependent diabetes (type II diabetes). In this condition, patients have high blood sugar despite being able to produce insulin. In fact, in the initial stage of type II diabetes the levels of insulin are often above normal. Untreated or poorly treated diabetes produces numerous complications many of which can be considered as the acceleration of aging and degenerative diseases.
In one study, glucose tolerance and insulin action were investigated in Italian centenarians (persons over 100 years old). It was found that in centenarians both these parameters were at the same level as in adults under 50, and better than in elderly under 75. This indicates that centenarians had only a minimal shift in their energy homeostasis (i.e. a very slow central aging clock), which may have contributed to their longevity.
The good news is that many things can improve glucose tolerance and reduce insulin excess, and the bad news is that many things can do the opposite. The "bad guys" here are all forms of stress, physical inactivity, a diet high in saturated fat and low in fiber, overeating, and, possibly, deficiencies of some nutrients, such as chromium; the "good guys" are exercise, losing excess weight, a diet low in saturated fat and high in fiber, and, possibly, correcting nutrient deficiencies.
Age-related disturbance in stress response is another major contributor to the aging process. According to the neuroendocrine theory of aging, the hypothalamus gradually loses its responsiveness to the feedback inhibition by corticosteroids, the key stress hormones produced and released by the adrenals (the most important corticosteroid in humans is cortisol). As a result, older individuals tend to produce more corticosteroids than young people in response to the same stressor (a situation, exposure or impact causing stress). Some older individuals have too much corticosteroids in their bloodstream even in the absence of stressors, which is physiologically equivalent to living in the state of chronic stress. There seems to exist a vicious circle: the central aging clock gradually disturbs normal stress response, which, in turn, accelerates the clock itself. In particular, corticosteroid excess contributes to glucose intolerance, depresses the immune system, elevates blood pressure, and in one way or the other contributes to essentially all age-related diseases.
In addition to insulin excess, impaired carbohydrate tolerance and abnormal stress response the central aging clock seems to contribute to many other age-related disturbances, including production of sex hormones, abnormal appetite regulation and so forth.
What can be done to slow the central aging clock? Bascially, whatever improves the sensitivity of the hypothalamus to the negative feedback from the rest of the body slows the clock down. Unfortunately, relatively little research has been tone to find effective practical ways to do that. The available research indicates that the levels of neurotransmitters (chemicals that carry messages between brain cells) in the hypothalamus is directly related to its responsiveness to negative feedback. Conversely, whatever raises neurotransmitter levels in the hypothalamus tends to slow down the aging clock. The table below lists the factors that seems to slow down or speed up the central aging clock
| Acceleration of the central aging clock is associated with: |
Slow down of the central aging clock is associated with: |
| Stress; abnormal response to stress |
Improving stress resistance; restoration of optimal response to stress; avoidance of intense or prolonged stress |
| Overeating, excess calories |
Caloric restriction (in rodents), maintenance of ideal body weight (in humans) |
| Impaired carbohydrate tolerance |
Improved carbohydrate tolerance |
| Insulin excess |
Optimal insulin release |
| Depression; decreased neurotransmitter levels in the hypothalamus |
Optimal emotional state, elevation of neurotransmitter levels in the hypothalamus |
| Lack of melatonin and other pineal gland hormones |
Restoration of the levels of melatonin and other pineal gland hormones |
| Free radical damage to the brain due to oxidation, ionizing radiation or environmental toxins. |
Prevention of free radical damage to the brain |
