A rat model system to study complex disease risks, fitness, aging, and longevity

The association between low exercise capacity and all-cause morbidity and mortality is statistically strong yet mechanistically unresolved. By connecting clinical observation with a theoretical base, we developed a working hypothesis that variation in capacity for oxygen metabolism is the central mechanistic determinant between disease and health (aerobic hypothesis). As an unbiased test, we show that two-way artificial selective breeding of rats for low and high intrinsic endurance exercise capacity also produces rats that differ for numerous disease risks, including the metabolic syndrome, cardiovascular complications, premature aging, and reduced longevity. This contrasting animal model system may prove to be translationally superior relative to more widely used simplistic models for understanding geriatric biology and medicine.     

Androgens, aging, and Alzheimer's disease

Testoterone depletion is a normal consequence of aging in men that is associated with senescent effects in androgen-responsive tissues. We discuss new evidence that one consequence of testosterone depletion in men is an increased risk for the development of Alzheimer's disease (AD). Furthermore, we discuss two candidate mechanisms by which test osterone may affect AD pathogenesis. First, testosterone has been identified as an endogenous regulator of β-amyloid, a protein that abnormally accumulates in AD brain and is implicated as a causal factor in the disease. Second, findings from several different paradigms indicate that testosterone has both neurotrophic and neuroprotective functions. These new findings support the clinical evaluation of androgen-based therapies for the prevention and treatment of AD.     

Growth factors, nutrient signaling, and cardiovascular aging

Growth factors regulated by specific macronutrients have been shown to promote aging and accelerate mortality in the majority of the organisms studied. In particular, the enzymes activated by growth hormone, insulin, and insulin-like growth factor-1 in mammals and their orthologs in simple model organisms represent perhaps the best-understood proteins involved in the aging process. Dietary restriction, which reduces the level of insulin-like growth factor-1 and of other growth factors, has been associated with protection from diabetes, cancer, and cardiovascular diseases, and deficiencies in growth hormone signaling and insulin-like growth factor-1 are strongly associated with protection from cancer and diabetes in both mice and humans; however, their role in cardiac function and cardiovascular diseases is controversial. Here, we review the link between growth factors, cardiac function, and heart disease with focus on the cardioprotective and sensitizing effect of growth factors in both model organisms and humans.     

Growth hormone and aging

Although age-related decline in plasma growth hormone (GH) levels is well documented, the possible role of GH in the control of aging is controversial. Overexpression of GH in transgenic mice is associated with reduced life expectancy and numerous symptoms of premature aging. Ames dwarf mice with hereditary GH, prolactin, and thyrotropin deficiency live much longer than their normal siblings. In contrast to these indications that GH may accelerate aging, some physiological changes in the elderly resemble symptoms of GH deficiency and can be corrected by GH replacement. It is suggested that these seemingly contradictory observations are related to the dose-response characteristics of GH action, and to negative correlation between body size and life expectancy within a species. Physiological mechanisms linking plasma GH levels and body size with aging remain to be identified.     

Growth hormone and aging

Aging is associated with a significant decline in secretion of growth hormone. This in turn leads to reduced circulating IGF-I and changes in IGF-binding proteins. Growth hormone replacement to growth hormone-deficient individuals has been shown to improve quality of life, enhance bone and muscle mass, and reduce cardiovascular risk. However, studies with growth hormone therapy in the elderly have been somewhat disappointing with minimal changes in lean body mass, musculoskeletal function, and overall quality of life. Moreover, recent evidence suggests that high normal serum IGF-I levels may be associated with a greater risk of several neoplastic disorders. Hence, there is less enthusiasm for reversing the changes of the “somatopause” with recombinant growth factors. An overview of these issues and the prospects for the future will be discussed in this article.     

Growth hormone and aging

The potential usefulness of growth hormone (GH) as an anti-aging therapy is of considerable current interest. Secretion of GH normally declines during aging and administration of GH can reverse age-related changes in body composition. However, mutant dwarf mice with congenital GH deficiency and GH resistant GH-R-KO mice live much longer than their normal siblings, while a pathological elevation of GH levels reduces life expectancy in both mice and men. We propose that the actions of GH on growth, development, and adult body size may serve as important determinants of aging and life span, while the age-related decline in GH levels contributes to some of the symptoms of aging.     

Stress management, aging, and disease.

The association of stress management, work, and individual factors with the incidence of upper-back disorders and coronary heart disease was studied according to the House paradigm of stress research. The features of work concerned its organization and social environment. Stress management and individual factors covered coping styles, sense of coherence, family roles, gender, and age. These factors were measured by questionnaire studies in 1992 when the subjects (n = 1101, mean age 58 years) were active workers, and again in 1997. Manageability and withdrawal stress response prevented upper-back disorders, whereas dissatisfaction with the work schedule predicted these disorders. Male gender predicted coronary heart disease.     

Polyamines in aging and disease

Polyamines are polycations that interact with negatively charged molecules such as DNA, RNA and proteins. They play multiple roles in cell growth, survival and proliferation. Changes in polyamine levels have been associated with aging and diseases. Their levels decline continuously with age and polyamine (spermidine or high-polyamine diet) supplementation increases life span in model organisms. Polyamines have also been involved in stress resistance. On the other hand, polyamines are increased in cancer cells and are a target for potential chemotherapeutic agents. In this review, we bring together these various results and draw a picture of the state of our knowledge on the roles of polyamines in aging, stress and diseases.     

Growth hormone,insulin-like growth factor-1 and the aging cardiovascular system

There is a large body of evidence that biological aging is related to a series of long-term catabolic processes resulting in decreased function and structural integrity of several physiological systems, among which is the cardiovascular system. These changes in the aging phenotype are correlated with a decline in the amplitude of pulsatile growth hormone secretion and the resulting decrease in plasma levels of its anabolic mediator, insulin like growth factor-1 (IGF-1). The relationship between growth hormone and biological aging is supported by studies demonstrating that growth hormone administration to old animals and humans raises plasma IGF-1 and results in increases in skeletal muscle and lean body mass, a decrease in adiposity, increased immune function, improvements in learning and memory, and increases in cardiovascular function. Since growth hormone and IGF-1 exert potent effects on the heart and vasculature, the relationship between age-related changes in cardiovascular function and the decline in growth hormone levels with age have become of interest. Among the age-related changes in the cardiovascular system are decreases in myocyte number, accumulation of fibrosis and collagen, decreases in stress-induced cardiac function through deterioration of the myocardial conduction system and beta-adrenergic receptor function, decreases in exercise capacity, vessel rarefaction, decreased arterial compliance and endothelial dysfunction leading to alterations in blood flow. Growth hormone has been found to exert potent effects on cardiovascular function in young animals and reverses many of the deficits in cardiovascular function in aged animals and humans. Nevertheless, it has been difficult to separate the effects of growth hormone deficiency from age-related diseases and associated pathologies. The development of novel animal models and additional research are required in order to elucidate the specific effects of growth hormone deficiency and assess its contribution to cardiovascular impairments and biological aging.     

Kidney disease in aging

There is an increasing number of elderly patients with glomerulonephritis. A number of reports regarding renal function [1–9] and morphology [10–13] in aged people have been published. However, few studies have been reported on the effect of glomerulonephritis on the kidneys of aged patients. Recently, some articles concerning renal function and histological changes in aged nephritic patients were reported [14]. Several reports about the effects of aging in an experimental kidney disease model [15–23] and on cultured renal cells [22, 24, 25] have been published. This review will focus mainly on the mechanisms of the decrease in renal function and morphological changes with aging.     

Neuroendocrine biomarkers of aging in the rat

The genome and environmental agents are believed to regulate aging processes mainly via the homeostatic and integrative mechanisms of the body, which consist primarily of the neuroendocrine, immune and cell-to-cell communicating systems. Of these, the neuroendocrine system is considered to be the most important since it regulates to a greater or lesser degree all body functions, in old age as well as in early and mature life. We have studied mainly three aging events in the rat: the reproductive decline, development of numerous mammary and pituitary tumors and the decrease in GH secretion and protein synthesis. We have found that all three are caused primarily by faults that develop in hypothalamic function, particularly the decline in norepinephrine (NE) and dopamine (DA) activity. This decline appears to be caused largely by damage to hypothalamic neurons as a result of the chronic action of hormones, toxins, free radicals, cross linkages, lipofuscin accumulation and "wear and tear". Administration of drugs that increase hypothalamic NE and DA activity can delay or reverse all three aging events. Changes in hormone secretion, estrous cycles, tumor development and protein synthesis can be measured and used as "biomarkers of aging" in the rat.