Toward a Biological Definition of Aging

Aging may be defined as a progressive loss of entropy and fractality (7). In clinical terms, the loss of entropy indicates a progressive decline in a person's functional reserve of different organs and systems; loss of fractality implies increasing difficulty in negotiating the living environment, due mainly to inadequate coordination of different functions. The increasing frequency of falls in the older aged person, despite the absence of focal neurological deficits and muscular weakness, may be considered an example of loss of fractality. A number of biological, physiological, medical, and functional changes underlie the loss of entropy and fractality.

Cellular and Molecular Changes of Aging

Cellular aging may be associated with changes typical of early stage carcinogenesis and include epigenetic changes, such as DNA hypermethylation, formation of

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Year

Age in years

<50 0

H 65-74 ran >85

ES350-64 E

a 75-84

FIGURE 1 Current and projected cases of cancer in the elderly.

DNA adducts, point mutation, and chromosomal translocation (8). Other changes may prevent carcinogenesis and include progressive shortening of telomeres and reduced cell proliferation and cell survival (9). The origin of these changes is not clear and may include exposure to environmental carcinogens, micro-environmental changes, including chronic inflammation (10), and emergence of apoptosis-resistant genotypes with more prolonged cellular survival as normal genotypes, which are more common then progressively wane as an effect of apop-tosis (11). In experimental animals, where they were mostly studied, these changes are, to some extent, tissue-specific and are particularly common in the skin and lymphatic system (8).

Of special interest is the proliferative senescence of fibroblasts "in vitro" (12). At the same time they lose their self-replicative ability, these cells seem to lose the ability to undergo apoptosis, and they start producing a number of tumor growth factors and lytic enzymes (metalloproteinase) that may promote the growth and spread of cancer.

Systemic Changes of Aging

These include chronic inflammation, immune senescence, endocrine senescence, and possibly increased levels of circulating growth factors and metalloproteinases from senescent stromal fibroblasts.

The role of chronic inflammation in aging is well established, and according to some investigators, aging is a chronic and progressive inflammation (10). Interleukin 6 (IL6) has been the most studied of inflammatory markers. Circulating levels of IL6 are elevated in the presence of several geriatric syndromes, including dementia, osteoporosis, failure to thrive, unexplained anemia, sarcopenia, and functional disability (13,14). Other inflammatory cytokines were found elevated in the circulation of individuals affected by different forms of cognitive disorders (15). In home-dwelling individuals aged 70 and over, increased circulating levels of IL6 and of D-dimer heralded the increased risk of death and of functional dependence (14). It has recently been shown that chronic inflammation may favor the development of precancerous genomic abnormalities; so, it is not far-fetched to assume that chronic inflammation may underlie some of the genomic changes of aging (16). The cancer preventative effects of COX 1 and 2 inhibitors may be explained, in part, by the antiflogistic effect of these substances.

Reduced production of sexual hormones by the gonads is the most obvious manifestation of endocrine senescence and may affect development and growth of hormone-dependent tumors, such as prostatic, mammary, and endometrial cancer. It is important to remember that the activity of sexual hormones is also influenced by body size and shape. With aging, abdominal deposition of fat becomes more common and is associated with increased aromatization of androgens and circulating levels of estrogens (17). In addition, abdominal obesity is associated with decreased concentrations of sexual hormone-binding proteins in the circulation (17). For this reason, obesity may favor the development of breast cancer in postmenopausal women and favor its recurrence after surgery. Obesity may also be associated with increased insulin resistance, increased circulating levels of insulin and, consequently, of growth hormone and of insulin-like growth factor 1 (IGF-1), that is, a powerful growth stimulator of several tumors (18). The circulating levels of corticosteroids appear increased in the older person, probably as a result of chronic inflammation (19).

Immune senescence involves an accumulation of so-called "memory" cells and a decline of T-cell mediated immunity and possibly of antigen presenting cells activity (20). The effects of immune senescence on tumor growth appear variable. In the experimental system, immune senescence appears to be associated with accelerated growth of highly immunogenic tumors, such as radiation-induced sarcoma, but with decreased growth of poorly immunogenic tumors, such as Lewis lung carcinoma (LLC) or B16 melanoma (21).

Physiological Changes of Aging

The physiological changes of aging include a reduced functional reserve of multiple organs and systems and, consequently, increased susceptibility to different forms of stress. These may comprise cancer treatment with surgery, radiation therapy, or cytotoxic chemotherapy. Of special interest is the decline in function of organs that are involved in drug metabolism and excretion or that are targets of drug toxicity. For example, the glomerular filtration rate is almost universally reduced with age, which indicates adjustments of the doses of medications excreted through the kidneys (22). Likewise, hepatic uptake and metabolism of drugs become altered with age, but the pharmacokinetics implications in cancer treatment are not well appreciated.

The organs and systems that are more vulnerable to the toxicity of chemotherapy with aging include the hemopoietic system, the mucosas, the heart, and the peripheral and central nervous systems (22).

The Concept of Frailty

The term frailty is commonly associated with the idea of aging. It is important to note that no agreement exists on the definition of frailty and that this term has been used to indicate two very different situations. One situation involves a critical reduction of functional reserve that does not impair the independence of the person, but makes the person more susceptible to the consequence of stress (23). This is the term that is gaining more general acceptance and may be utilized in the future in oncology to designate individuals for whom special care is indicated to minimize the complications of treatment. The other situation is one where the functional reserve is so critically reduced that it is barely sufficient to keep the person alive (24). In this case, symptom management is the only reasonable form of treatment, as the patient would not be able to tolerate even minimal stress. This disagreement on the meaning of frailty reflects some general agreement on how aging should be construed and approached clinically: aging represents a progressive loss of functional reserve; loss of functional reserve may lead to loss of independence, that is, an older person may become unable to live without social support.

Some important landmarks may be recognized on the trajectory of aging that may influence medical as well as social intervention. These include a situation

Genetics

Environmental

factors:

• Disease

♦ Stress

• Toxic

r

substances

1

Damage to specific organs and systems

Damage to specific organs and systems

FIGURE 2 Trajectory of aging.

Chronic inflammation of increased vulnerability to environmental stress, including aggressive medical treatment, and a condition in which the functional reserve is almost exhausted and in which preservation of comfort is the only realistic goal. The recognition of these landmarks and the definition of situations in between are one of the most important challenges in the management of older individuals. Current methods of evaluation include medical, functional, and performance evaluation and, more recently, some laboratory tests including the determination of circulating levels of inflammatory cytokines (25). Figure 2 summarizes the concepts described in this section.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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