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I.R.F. / Aging news / General / 04081301

Metabolic Age Remodeling
Posted on: August 13, 2004

In 1989 a general theory was proposed that suggested that ageing is indirectly controlled by a network of cellular and molecular defense mechanisms, including heat shock proteins, DNA repair mechanisms, apoptosis, and - at a more integrated level - the immune and the neuroendocrine systems (the network theory of ageing). The aim of this theory was to combine suggestions of evolutionary theories of ageing and data emerging from cellular and molecular biology of ageing. One prediction of this hypothesis is that animal and humans capable of reaching an age close to the extreme limit of the life span characteristic for the species may be equipped with a very efficient network of anti-ageing mechanisms. Focusing on the human species, and to the changes occurring with age, some important organs of the endocrine system, such as the thyroid, and the human immune system, i.e. human immunosenescence, have been deeply investigated. In fact, it was been hypothesized that immunosenescence was responsible for alterations of the immune system affecting both antibody and cell-mediated responses. Moreover, immunosenescence may contribute to the most important age-associated pathologies such as cancer, neurodegenerative diseases, diabetes, osteoporosis and osteoarthritis, among others. Notwithstanding, the whole body of studies documented that immunosenescence is a simple deterioration that can be ruled out. Thus, a new paradigm, the remodeling theory of ageing, was proposed. This theory suggests that immunosenescence is the net result of the continuous adaptation of the body to the deteriorative changes occurring over time. According to this hypothesis, body resources are continuously optimized, and immunosenescence must be considered a very dynamic process including both loss and gain. Recent data suggested an evolutionary theory of immunosenescence. These studies regard the conservation of molecules mediating stress, innate immunity and inflammation throughout evolution, from invertebrate to man. The results suggest that these three phenomena are part of an integrated ancestral defense network of basic adaptive mechanisms critical for survival and body maintenance. Perspective data also indicate that ageing can be envisaged as a situation in which the most evolutionary recent and sophisticated defense mechanisms deteriorate with age, while the most evolutionary ancestral and gross mechanisms are conserved or up-regulated.
Ageing is frequently associated with impaired glucose handling, mainly due to a decline in insulin action. Age-related insulin resistance was due to receptor and postreceptor defects with a main reduction in oxidative glucose metabolism.
In explaining the relationship between ageing and insulin resistance one might encompass three main pathways:
1. Anthropometric changes (relative and absolute increase in body fat combined with a decline in fat-free mass), which could be the anatomic substrate for explaining the reduction in active metabolic tissue;
2. Age-related changes in several plasma endocrine and metabolic parameters (decline in plasma dehydropiadrosterone sulfate (DHEAS) and insulin-like growth factor (IGF-1) and rise in plasma leptin and oxidative stress), which might counteract the effect of insulin at skeletal muscle and adipose tissue levels;
3. A possible specific genetic background.

One should point out that age-related insulin resistance has also a strong clinical relevance because hyperinsulinemia/insulin resistance has been shown to predict multiple atherogenic changes in lipoprotein and to be associated with a more elevated prevalence of coronary heart disease in non-diabetic and diabetic aged subjects. As cardiovascular diseases are still the first cause of death in human beings, a preserved insulin action might be associated with a lower incidence of fatal and nonfatal cardiovascular events in the elderly. Despite the lack of clinical trials investigating the protective affect of insulin sensitizers towards coronary heart diseases in the elderly, it is now accepted that age related insulin resistance is not an obligatory finding. In other words, a poor or a preserved insulin action in the elderly might be the result of an unsuccessful or successful metabolic age remodeling, respectively. A dramatic support to such hypothesis comes from the in vivo measurements of insulin action in healthy centenarians (HC). HC had an insulin mediated glucose uptake greater than one in aged subjects and not different from one found in adults. Furthermore, HC had a preserved effect of insulin not restrained to the glucose metabolism but also present at adipose tissue level. In fact, insulin infusion was normally associated with an inhibition of lipolysis and thus to a significant decline in plasma free fatty acid and triglyceride concentrations (Fig. 1).


Fig. 1. (a) Insulin mediated glucose uptake, (b) changes in plasma triglycerides and (c) changes in free fatty acids (FFA) (in adults, aged subject and healthy centenarians).

Comparing adults, aged subjects and HC, the inhibitory effect of insulin on lipolysis was similar in adults and HC; in contrast, aged subjects displayed impaired insulin mediated lowering effect on plasma free fatty acid and triglyceride concentrations (Fig. 1).
A further parameter widely involved in the genesis of coronary heart disease is oxidative stress. One should point out that the relationship between oxidative stress and metabolic derangements is strengthened by the in vitro and in vivo evidence that elevated oxidative stress is caused by hyperglycemia, by insulin resistance by hypercholesterolemia, by a decline in antioxidant defense and by advancing age. Once again this seems to not be the case of HC.
In this latter group of HC subjects, all indices of oxidative stress (lipid peroxides, thiobarbituric reactive substance, oxidized/reduced gluthatione ratio) were lower than in aged subjects and in between those of aged subjects and adults. Interestingly, plasma vitamin E concentration, a well-known antioxidant vitamin, resulted greater in HC than in aged subjects. Due to the strong impact, that free radicals may have on cardiovascular apparatus and, in particular, on endothelium function, the potential difference in arterial blood pressure and in nitric oxide activity has been also evaluated in aged subjects and in HC. As expected, HC had a lower arterial blood pressure and a better endothelial function than aged subjects. The lack of insulin resistance and of elevated oxidative stress in HC should be considered the living evidence that a successful metabolic age remodeling might provide a contribution for the extreme life span in this special group of subjects.

Anthropometric factors that account for metabolic age-remodeling

Significant quantitative and qualitative changes occur in the body composition with ageing. There is a slow, progressive redistribution of fat in the elderly as intra-abdominal fat tends to increase and subcutaneous fat on the limbs tends to decrease. This is reflected in a decline in limb skinfold thickness. Less subcutaneous adipose tissue and significantly more intra-abdominal adipose tissue are found in older men. This result is in agreement with the evidence that age-related insulin resistance is associated with age-related rise in plasma free fatty acid concentrations, a phenomenon frequently occurring in people with increased intra-abdominal fat.
An age related increase in body mass index (BMI) might be an additional factor favoring a decline in insulin sensitivity. Moreover, an increase in body fat is a condition that is per se associated with insulin resistance, so that the contemporary presence of old age and high body fat may worsen or highlight a hidden metabolic problem.
If anthropometric characteristics play a role in the worsening of metabolic control in the elderly, one would expect that HC have anthropometric characteristics different from those commonly reported in the elderly. HC have a free fat mass (FFM) not different from aged subjects but lower than adults. HC had a WHR (body fat distribution as waist/hip ratio) lower than aged subjects but not different from adults. When adjusted for age and sex, WHR was still lower in HC than in aged subjects. Such data in HC seems in contrast to the results in aged subjects. One would expect HC to have a further age-dependent decline in FFM and increase in body fat. Body fat distribution is also an anthropometric parameter whose change indicates a poor individual complaining to the change in age-related needs in energy intake, requirements and expenditure. In fact, a rise in WHR and thus a more central body fat distribution is associated with a worsening of glucose metabolism, dyslipidemia and a greater prevalence and incidence of cardiovascular diseases. It should be pointed out that the relationship between elevated WHR and insulin resistance or dyslipidemia has been found in aged subjects but not in HC.
Thus, if successful ageing is to keep anthropometric characteristics protective against cardiovascular and cancer diseases, one would have to conclude that HC are the best living model to show our hypothesis operative in human beings.

Endocrine factors that account for the metabolic age remodeling

Insulin-like growth factor-1 (IGF-1) shares positive effects at anthropometric and metabolic levels. In fact, elevated plasma IGF-1 concentrations are associated with a low body fat content, increased muscular mass and improved gluco and lipid metabolic control. Thus, one cannot exclude that IGF-1 has a role in the age remodeling and, in particular, it is, at least jointly responsible for the anthropometric and metabolic difference occurring between aged subjects and HC. The study of potential role of IGF-1 on explaining the difference between aged subjects and HC provides evidence that plasma total IGF-1 was similar in aged subjects and HC while insulin-like growth factor binding protein-3 (IGFBP-3) was lower in HC than in aged subjects. Thus, the plasma IGF-1/IGFBP-3 molar ratio – expression of the free plasma IGF-1 concentration – was more elevated in HC than in aged subjects.
Leptin is the product of the ob/ob gene that has been shown to regulate body weight and food intake. Hyperleptinemia is the result of an unbalanced ratio between leptin overproduction (by adipose tissue) and a peripheral leptin resistance at hypothalamic level and is associated with elevated energy intake and obesity. Since HC eat less than aged subjects and have a more favorable body fat content and distribution, one can hypothesize that the difference in plasma leptin concentration may go towards explaining such differences. Indeed, plasma leptin concentration in HC was in between that of adults and aged subjects and positively correlated with body mass index and body fat content. Thus, HC were characterized by a lower leptin production and/or better hypothalamic sensitivity than aged subjects are. Both phenomena might contribute to keeping energy intake under control and to avoid a rise in body fat content in HC.
Dehydroepiandrosterone sulfate (DHEAS) is a steroid hormone precursor of testosterone. DHEAS has also been indicated as an anti-ageing hormone due to its powerful antioxidant qualities. As DHEAS levels decline with advancing age, the hypothesis that DHEAS might also have a role in metabolic-age remodeling in HC is intriguing. Thus, plasma DHEAS concentration has been determined in a large group of subjects with a wide age range. As expected, plasma DHEAS progressively declines with advancing age but no differences between HC and aged subjects were found. So, it was concluded that plasma DHEAS does not play a major modulator role on age-metabolic remodeling in HC.

Do genetic factors account for metabolic age remodeling?

To explore the role of inherited factors in successful ageing it may be useful to identify the genes that contribute to human longevity; thus, alleles pools at polymorphic candidate loci were compared between individuals selected for longevity and younger people from the same race and country. Indeed, if a certain locus affects life expectancy, the gene pool of extremely old individuals should be different from that of younger people because of a slow change in the composition of the genotype pool that takes place as survival selection operates. By means of this approach, significant longevity/allele associations have been found at HLA, ACE, THO and mtDNA. Interestingly enough, a significant age-related change in the genotypic pool has also been observed for ApoB, which is a major apoprotein responsible for total cholesterol metabolism. Conducted study showed that ApoB is protective in the physiological scenario of youth individuals, but then becomes frail in the new physiological scenario that emerges with increasing age. The central role played by ApoB in cell cholesterol homeostasis (fundamental in membrane synthesis as well as in steroid hormogenesis) may explain the age-related effect of the ApoB locus on survival. Small changes in cholesterol homeostasis, which accumulate with age, may account for such a model. It should be also pointed out that elevated plasma total cholesterol concentration is a powerful risk factor for coronary heart disease, which is still the first cause of death in aged subjects.
The culmination of such data led us to suggest that a genetic background might contribute to determining the extreme longevity; the role of genetics is most likely magnified by an appropriate interaction with the environmental, especially with life-style. Concerning the role of a specific genetic background on metabolic age remodeling, the studies reported above might be useful to outline a target that still has to be accurately hit.

Evidence has demonstrated that, starting from young to very old subjects, ageing is associated with a progressive remodeling. Such age remodeling mainly affects anthropometric, endocrine and thus metabolic factors such as plasma lipid profile and insulin action. Age remodeling is a very important process as it allows a resetting of body function in relation to advancing age. Age remodeling is a physiological process occurring in the whole population. Indeed, such phenomenon occurs in some individuals successfully, and in others unsuccessfully. Healthy centenarians in whom age remodeling occurs without any problems represent the successful case. In the all others cases, different degrees of unsuccessful age remodeling (from an early to a later occurrence of a diseases) may occur. Why and how aged subjects become centenarians is still unknown. Life-style and a genetic background that is potentially protective against the age related metabolic derangement might contribute to a successfully metabolic age remodeling. Whether the mechanism of metabolic age remodeling is environmental, genetic or both, the lesson coming from HC is that longer life is associated with a successful age-remodeling. How we can reach such a target is the challenge for the geriatric research in the next century and only future longitudinal studies will provide a solid and reliable response to such a question.

Source: G. Paolisso, M. Barbieri, M. Bonafe and C. Franceschi; Metabolic age modeling: the lesson from centenarians; European Journal of Clinical Investigation (2000) 30, 888-894
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