Ageing Abstracts 11

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Hormone treatments and preventive strategies in the aging male: whom and when to treat
            (Heaton, 2003) Download
Sex hormones have a broad range of actions in regulating very diverse systems throughout life. Testosterone and other related hormones change with age to varying degrees and may induce pathophysiological changes and the clinical condition known as andropause. Androgen replacement is the accepted but not the only possible treatment for andropause. The presence of clinical symptoms, including a loss of sexual function, intellectual capacity, lean body mass, or bone mineral density; alterations in body hair, skin, or sleep pattern; or increases in visceral fat, together with low levels of serum testosterone characterize andropause. An appreciation of the potentially undesirable impact of androgens on the biology of prostate cancer, as well as possibly the cardiovascular system, is necessary. However, proper evaluation of aging men with symptoms of andropause will result in a decision to initiate androgen therapy in some aging men.

Aging biology and geriatric clinical pharmacology.
            (McLean and Le Couteur, 2004) Download
Population aging evokes doomsday economic and sociological prognostication, despite a minority of older people suffering significant dependency and the potential for advances in therapeutics of age-related disease and primary aging. Biological aging processes are linked mechanistically to altered drug handling, altered physiological reserve, and pharmacodynamic responses. Parenteral loading doses need only be adjusted for body weight as volumes of distribution are little changed, whereas oral loading doses in some cases may require reduction to account for age-related increases in bioavailability. Age-related reduction of hepatic blood flow and hepatocyte mass and primary aging changes in hepatic sinusoidal endothelium with effects on drug transfer and oxygen delivery reduce hepatic drug clearance. Primary renal aging is evident, although renal clearance reduction in older people is predominantly disease-related and is poorly estimated by standard methods. The geriatric dosing axiom, "start low and go slow" is based on pharmacokinetic considerations and concern for adverse drug reactions, not from clinical trial data. In the absence of generalizable dosage guidelines, individualization via effect titration is required. Altered pharmacodynamics are well documented in the cardiovascular system, with changes in the autonomic system, autacoid receptors, drug receptors, and endothelial function to modify baseline cardiovascular tone and responses to stimuli such as postural change and feeding. Adverse drug reactions and polypharmacy represent major linkages to avoidable morbidity and mortality. This, combined with a deficient therapeutic evidence base, suggests that extrapolation of risk-benefit ratios from younger adults to geriatric populations is not necessarily valid. Even so, therapeutic advances generally may convert healthy longevity from an asset of fortunate individuals into a general social benefit.

Ageing and longevity are related to growth hormone/insulin-like growth factor-1 secretion.
            (Ruiz-Torres and Soares de Melo Kirzner, 2002) Download
BACKGROUND:  It is known that the growth process is related to an individual's life-span, but the role of growth hormone (GH) secretion in human ageing remains unknown. OBJECTIVE:  This study has focussed on the influence of GH on ageing parameters and on its relationship with human longevity. METHODS:  To deal with the first issue, we compared ageing parameters of young (up to 39) and old (over 70) individuals having similar insulin-like growth factor-1 (IGF-1) blood levels. For the second one, the decline in IGF-1 levels was studied comparing its behaviour in the first half with that in the second half of adult life. The latter represents the period of life in which mortality progressively increases. Two hundred and five healthy individuals were chosen as subjects, well distributed by gender and age (between 19 and 93 years). RESULTS:  Old males with IGF-1 levels similar to young ones do not show the age-dependent decrease in serum testosterone and lean body mass, nor the increase in fat body mass. Other hormone-metabolic and nutritional parameters do not reveal any change compared with the results of all individuals. In females, the results do not allow to assume any IGF-1 influence. The behaviour of the linear regression in the second half of adult life of males, which becomes flat because old men having low IGF-1 blood levels die earlier, is consistent with these results. This effect, which is supported by predictive analysis, is not observed in females, i.e. the IGF-1 level declines in the second half of the women's adult life are only a little flatter than in the first half. Finally, extrapolating the regressions obtained in the first half of adulthood, the age at which the curve crosses the x-axis is 110 years for males and 132 for females. CONCLUSIONS:  The presented study of IGF-1 levels suggests that the GH secretion in adulthood plays a determinant role not only for some regressive manifestations, but also for life potential.

Off-label use of hormones as an antiaging strategy: a review.
            (Samaras et al., 2014) Download
Given demographic evolution of the population in modern societies, one of the most important health care needs is successful aging with less frailty and dependency. During the last 20 years, a multitude of anti-aging practices have appeared worldwide, aiming at retarding or even stopping and reversing the effects of aging on the human body. One of the cornerstones of anti-aging is hormone replacement. At present, women live one third of their lives in a state of sex-hormone deficiency. Men are also subject to age-related testosterone decline, but andropause remains frequently under-diagnosed and under-treated. Due to the decline of hormone production from gonads in both sexes, the importance of dehydroepiandrosterone (DHEA) in steroid hormone production increases with age. However, DHEA levels also decrease with age. Also, growth hormone age-associated decrease may be so important that insulin growth factor-1 levels found in elderly individuals are sometimes as low as those encountered in adult patients with established deficiency. Skin aging as well as decreases in lean body mass, bone mineral density, sexual desire and erectile function, intellectual activity and mood have all been related to this decrease of hormone production with age. Great disparities exist between recommendations from scientific societies and actual use of hormone supplements in aging and elderly patients. In this article, we review actual data on the effects of age related hormone decline on the aging process and age-related diseases such as sarcopenia and falls, osteoporosis, cognitive decline, mood disorders, cardiovascular health and sexual activity. We also provide information on the efficiency and safety of hormone replacement protocols in aging patients. Finally, we argue on future perspectives of such protocols as part of everyday practice.

Dehydroepiandrosterone, glucose-6-phosphate dehydrogenase, and longevity.
            (Schwartz and Pashko, 2004) Download
Dehydroepiandrosterone (DHEA) is an abundantly produced adrenal steroid whose biological role has never been clarified. DHEA is a potent uncompetitive inhibitor of mammalian glucose-6-phosphate dehydrogenase (G6PDH) and as a consequence lowers NADPH levels and reduces NADPH-dependent oxygen-free radical production. Overproduction of oxygen-free radicals, or oxidative stress, upregulates inflammation and cellular proliferation and is believed to play a critical role in the development of cancer, atherosclerosis, and Alzheimer's disease, as well as the basic aging process. Both in vitro and in vivo experimental studies strongly indicate that DHEA and related steroids inhibit inflammation and associated epithelial hyperplasia, carcinogenesis, and atherosclerosis, at least in part, through the inhibition of G6PDH and oxygen-free radical formation. Recent epidemiological findings in Sardinian males bearing the Mediterranean variant of G6PDH deficiency are consistent with the hypothesis that reduced G6PDH activity has a beneficial effect on age-related disease development and longevity. Clinical trials with DHEA are encumbered by the high oral doses required as well as the conversion of DHEA into active androgens. The use of less androgenic congeners as well as non-oral formulations may facilitate testing of this class of compounds.


 

The rate of change in declining steroid hormones: a new parameter of healthy aging in men
            (Walther et al., 2016) Download
Research on healthy aging in men has increasingly focused on age-related hormonal changes. Testosterone (T) decline is primarily investigated, while age-related changes in other sex steroids (dehydroepiandrosterone [DHEA], estradiol [E2], progesterone [P]) are mostly neglected. An integrated hormone parameter reflecting aging processes in men has yet to be identified. 271 self-reporting healthy men between 40 and 75 provided both psychometric data and saliva samples for hormone analysis. Correlation analysis between age and sex steroids revealed negative associations for the four sex steroids (T, DHEA, E2, and P). Principal component analysis including ten salivary analytes identified a principal component mainly unifying the variance of the four sex steroid hormones. Subsequent principal component analysis including the four sex steroids extracted the principal component of declining steroid hormones (DSH). Moderation analysis of the association between age and DSH revealed significant moderation effects for psychosocial factors such as depression, chronic stress and perceived general health. In conclusion, these results provide further evidence that sex steroids decline in aging men and that the integrated hormone parameter DSH and its rate of change can be used as biomarkers for healthy aging in men. Furthermore, the negative association of age and DSH is moderated by psychosocial factors.

Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice.
            (Yuan et al., 2018) Download
Aging is known as a major risk factor for the structure and function of the nervous system. There is urgent need to overcome such deleterious effects of age-related neurodegeneration. Here we show that peripheral nerves of 24-month-old aging C57BL/6 mice of either sex show similar pathological alterations as nerves from aging human individuals, whereas 12-month-old adult mice lack such alterations. Specifically, nerve fibers showed demyelination, remyelination and axonal lesion. Moreover, in the aging mice, neuromuscular junctions showed features typical for dying-back neuropathies, as revealed by a decline of presynaptic markers, associated with α-bungarotoxin-positive postsynapses. In line with these observations were reduced muscle strengths. These alterations were accompanied by elevated numbers of endoneurial macrophages, partially comprising the features of phagocytosing macrophages. Comparable profiles of macrophages could be identified in peripheral nerve biopsies of aging persons. To determine the pathological impact of macrophages in aging mice, we selectively targeted the cells by applying an orally administered CSF-1R specific kinase (c-FMS) inhibitor. The 6-month-lasting treatment started before development of degenerative changes at 18 months and reduced macrophage numbers in mice by ∼70%, without side effects. Strikingly, nerve structure was ameliorated and muscle strength preserved. We show, for the first time, that age-related degenerative changes in peripheral nerves are driven by macrophages. These findings may pave the way for treating degeneration in the aging peripheral nervous system by targeting macrophages, leading to reduced weakness, improved mobility, and eventually increased quality of life in the elderly.

Metabolic syndrome and all-cause and cardiovascular mortality in an Italian elderly population: the Progetto Veneto Anziani (Pro.V.A.) Study.
            (Zambon et al., 2009) Download
OBJECTIVE:  The purpose of this study was to explore the association of metabolic syndrome and each of its components with all-cause and cardiovascular mortality in a general Italian elderly population. RESEARCH DESIGN AND METHODS:  Metabolic syndrome, diagnosed by National Cholesterol Education Program Adult Treatment Panel III criteria, all-cause mortality, and cardiovascular mortality, was evaluated in 2,910 subjects aged > or =65 years of the Progetto Veneto Anziani (Pro.V.A.) Study during a mean follow-up time of 4.4 years. RESULTS:  After multivariable adjustment, metabolic syndrome was associated with increased all-cause mortality in all subjects (hazard ratio 1.41 [95% CI 1.16-1.72], P = 0.001), among men (1.42 [1.06-1.89], P = 0.017), and among women (1.47 [1.13-1.91], P = 0.004). High glucose in all subjects (1.27 [1.02-1.59], P = 0.037) and in women (1.61 [1.16-2.24], P = 0.005) and low HDL cholesterol in women (1.48 [1.08-2.02], P = 0.014) were predictors of all-cause mortality, even independently of the interactions of different metabolic syndrome components. After multivariable adjustment, metabolic syndrome was also associated with increased cardiovascular mortality in all subjects (1.60 [1.17-2.19], P = 0.003), among men (1.66 [1.00-2.76], P = 0.051), and among women (1.60 [1.06-2.33], P = 0.025). High glucose (2.17 [1.28-3.68], P = 0.004) and low HDL cholesterol (1.78 [1.07-2.95], P = 0.026) among women predicted higher cardiovascular mortality. CONCLUSIONS:  In this general Italian elderly population, among metabolic syndrome components, all-cause mortality is better predicted by high glucose in all subjects and in women and by low HDL cholesterol in women, whereas cardiovascular mortality is better predicted by high glucose and low HDL cholesterol in women.

mTOR: from growth signal integration to cancer, diabetes and ageing.
            (Zoncu et al., 2011) Download
In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.

 


References

Heaton, JP (2003), ‘Hormone treatments and preventive strategies in the aging male: whom and when to treat’, Rev Urol, 5 Suppl 1 S16-21. PubMed: 16985938
McLean, AJ and DG Le Couteur (2004), ‘Aging biology and geriatric clinical pharmacology.’, Pharmacol Rev, 56 (2), 163-84. PubMed: 15169926
Ruiz-Torres, A and M Soares de Melo Kirzner (2002), ‘Ageing and longevity are related to growth hormone/insulin-like growth factor-1 secretion.’, Gerontology, 48 (6), 401-7. PubMed: 12393957
Samaras, N, et al. (2014), ‘Off-label use of hormones as an antiaging strategy: a review.’, Clin Interv Aging, 9 1175-86. PubMed: 25092967
Schwartz, AG and LL Pashko (2004), ‘Dehydroepiandrosterone, glucose-6-phosphate dehydrogenase, and longevity.’, Ageing Res Rev, 3 (2), 171-87. PubMed: 15177053
Walther, A, et al. (2016), ‘The rate of change in declining steroid hormones: a new parameter of healthy aging in men’, Oncotarget, 7 (38), 60844-57. PubMed: 27589836
Yuan, X, et al. (2018), ‘Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice.’, J Neurosci, 38 (19), 4610-20. PubMed: 29712789
Zambon, S, et al. (2009), ‘Metabolic syndrome and all-cause and cardiovascular mortality in an Italian elderly population: the Progetto Veneto Anziani (Pro.V.A.) Study.’, Diabetes Care, 32 (1), 153-59. PubMed: 18931101
Zoncu, R, A Efeyan, and DM Sabatini (2011), ‘mTOR: from growth signal integration to cancer, diabetes and ageing.’, Nat Rev Mol Cell Biol, 12 (1), 21-35. PubMed: 21157483