Ageing Abstracts 10

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The key role of growth hormone-insulin-IGF-1 signaling in aging and cancer.
            (Anisimov and Bartke, 2013) Download
Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors in aging. GH/Insulin/insulin-like growth factor-1 (IGF-1) signaling molecules that have been linked to longevity include daf-2 and InR and their homologues in mammals, and inactivation of the corresponding genes increases lifespan in nematodes, fruit flies and mice. The life-prolonging effects of caloric restriction are likely related to decreasing IGF-1 levels. Evidence has emerged that antidiabetic drugs are promising candidates for both lifespan extension and prevention of cancer. Thus, antidiabetic drugs postpone spontaneous carcinogenesis in mice and rats, as well as chemical and radiation carcinogenesis in mice, rats and hamsters. Furthermore, metformin seems to decrease the risk for cancer in diabetic patients.

Enhanced antioxidant capacity and anti-ageing biomarkers after diet micronutrient supplementation.
            (Balcerczyk et al., 2014) Download
A growing number of studies confirm an important effect of diet, lifestyle and physical activity on health status, the ageing process and many metabolic disorders. This study focuses on the influence of a diet supplement, NucleVital(R)Q10 Complex, on parameters related to redox homeostasis and ageing. An experimental group of 66 healthy volunteer women aged 35-55 supplemented their diet for 12 weeks with the complex, which contained omega-3 acids (1350 mg/day), ubiquinone (300 mg/day), astaxanthin (15 mg/day), lycopene (45 mg/day), lutein palmitate (30 mg/day), zeaxanthine palmitate (6 mg/day), L-selenomethionine (330 mg/day), cholecalciferol (30 microg/day) and alpha-tocopherol (45 mg/day). We found that NucleVital(R)Q10 Complex supplementation significantly increased total antioxidant capacity of plasma and activity of erythrocyte superoxide dismutase, with slight effects on oxidative stress biomarkers in erythrocytes; MDA and 4-hydroxyalkene levels. Apart from the observed antioxidative effects, the tested supplement also showed anti-ageing activity. Analysis of expression of SIRT1 and 2 in PBMCs showed significant changes for both genes on a mRNA level. The level of telomerase was also increased by more than 25%, although the length of lymphocyte telomeres, determined by RT-PCR, remained unchanged. Our results demonstrate beneficial effects concerning the antioxidant potential of plasma as well as biomarkers related to ageing even after short term supplementation of diet with NucleVital(R)Q10 Complex.

Ageing and diabetes: implications for brain function.
            (Biessels et al., 2002) Download
Diabetes mellitus is associated with moderate cognitive deficits and neurophysiological and structural changes in the brain, a condition that may be referred to as diabetic encephalopathy. Diabetes increases the risk of dementia, particularly in the elderly. The emerging view is that the diabetic brain features many symptoms that are best described as "accelerated brain ageing." The clinical characteristics of diabetic encephalopathy are discussed, as well as behavioural (e.g. spatial learning) and neurophysiological (e.g. hippocampal synaptic plasticity) findings in animal models. Animal models can make a substantial contribution to our understanding of the pathogenesis, which shares many features with the mechanisms underlying brain ageing. By unravelling the pathogenesis, targets for pharmacotherapy can be identified. This may allow treatment or prevention of this diabetic complication in the future. We discuss changes in glutamate receptor subtypes, in second-messenger systems and in protein kinases that may account for the alterations in synaptic plasticity. In addition, the possible role of cerebrovascular changes, oxidative stress, nonenzymatic protein glycation, insulin and alterations in neuronal calcium homeostasis are addressed.

Daily consumption of the collagen supplement Pure Gold Collagen(R) reduces visible signs of aging.
            (Borumand and Sibilla, 2014) Download
With age, changes in the metabolic processes of structural components of the skin lead to visible signs of aging, such as increased dryness and wrinkle formation. The nutritional supplement, Pure Gold Collagen((R)), which consists of hydrolyzed collagen, hyaluronic acid, vitamins, and minerals, was developed to counteract these signs. An open-label study was conducted to investigate the effects of this nutritional supplement on skin properties. Supplementation with 50 mL of Pure Gold Collagen on a daily basis for 60 days led to a noticeable reduction in skin dryness, wrinkles, and nasolabial fold depth. In addition, a significant increase in collagen density and skin firmness was observed after 12 weeks. The data from this study suggest that Pure Gold Collagen can counteract signs of natural aging.


 

Clinical aspects of thyroid function during ageing.
            (Chaker et al., 2018) Download
Globally, populations are ageing at a rapid rate. The increase in the number of older citizens is accompanied by an increased prevalence of thyroid dysfunction, one of the most common disorders in older people. However, the diagnosis of thyroid dysfunction in older people is hindered by several factors, including the scarcity of thyroid dysfunction symptoms in older people. We describe the physiological changes in thyroid function that occur with increasing age, focusing on literature regarding changes in thyroid function test results in older populations. We also discuss treatment considerations for clinical and subclinical thyroid dysfunction according to international guidelines for older people. Finally, we discuss the relationship between variations in thyroid function and common diseases of old age including cardiovascular disease, osteoporosis, cognitive impairment, and frailty and suggest directions for future research.

Frailty and the endocrine system.
            (Clegg and Hassan-Smith, 2018) Download
Frailty is a condition characterised by loss of biological reserves, failure of homoeostatic mechanisms, and vulnerability to adverse outcomes. The endocrine system is considered particularly important in frailty, because of its complex inter-relationships with the brain, immune system, and skeletal muscle. This Review summarises evidence indicating a key role for the hypothalamic-pituitary axis in the pathogenesis of frailty through aberrant regulation of glucocorticoid secretion, insulin-like growth factor signalling, and androgen production. Evidence also indicates a potential role for vitamin D and insulin resistance in the pathogenesis of frailty. The role of thyroid hormones in the pathogenesis of frailty remains uncertain. Key convergent pathological effects of frailty include loss of muscle mass and strength, with consequent impact on mobility and activities of daily living. Future translational research should focus on the understanding of endocrine mechanisms, to identify potential biomarkers of the condition, modifiable targets for treatment, and novel pharmacological drugs targeted at the endocrine components of frailty.

Health and disease in 85 year olds: baseline findings from the Newcastle 85+ cohort study.
            (Collerton et al., 2009) Download
OBJECTIVES: The Newcastle 85+ Study aims to systematically study the clinical, biological, and psychosocial attributes of an unselected cohort of 85 year olds and to examine subsequent health trajectories as the cohort ages; health at baseline is reported. DESIGN: Cross sectional analysis of baseline data from a cohort study. SETTING: Newcastle upon Tyne and North Tyneside primary care trusts, United Kingdom. PARTICIPANTS: 1042 people born in 1921 and registered with the participating general practices. MAIN OUTCOME MEASURES: Detailed health assessment and review of general practice records (disease, medication, and use of general practice services); participants could decline elements of the protocol. RESULTS: Of the 1453 eligible people, 851 (58.6%) were recruited to health assessment plus record review, 188 (12.9%) to record review only, and 3 (0.2%) to health assessment only. Data from record review are reported on a maximum of 1030 and from health assessment on a maximum of 853; individual denominators differ owing to withdrawal and missing values. Of the health assessment sample (n=853), 62.1% (n=530) were women and 10.4% (n=89) were in institutional care. The most prevalent diseases were hypertension (57.5%, 592/1030) and osteoarthritis (51.8%, 534/1030). Moderate or severe cognitive impairment was present in 11.7% (96/824) of participants, severe or profound urinary incontinence in 21.3% (173/813), hearing impairment in 59.6% (505/848), and visual impairment in 37.2% (309/831). Health assessment identified participants with possible disease but without a previous diagnosis in their medical record for hypertension (25.1%, 206/821), ischaemic heart disease (12.6%, 99/788), depression (6.9%, 53/772), dementia (6.7%, 56/840), and atrial fibrillation (3.8%, 30/788). Undiagnosed diabetes mellitus and thyroid disease were rare (1%, 7/717 and 6/762, respectively). A median of 3 (interquartile range 1-8) activities of daily living were undertaken with difficulty. Overall, 77.6% (646/832) of participants rated their health compared with others of the same age as good, very good, or excellent. High contact rates in the previous year with general practitioners (93.8%, 960/1024) were recorded. Women had significantly higher disease counts (medians: women 5, men 4; P=0.033) and disability scores (medians: women 4, men 2; P=0.0006) than men, but were less likely to have attended outpatient clinics in the previous three months (women 29% (150/524), men 37% (118/320), odds ratio 0.7, 95% confidence interval 0.5 to 0.9). CONCLUSIONS: This large cohort of 85 year olds showed good levels of both self rated health and functional ability despite significant levels of disease and impairment. Hypertension, ischaemic heart disease, atrial fibrillation, depression, and dementia may be underdiagnosed. Notable differences were found between the sexes: women outnumbered men and had more disease and disability.

Establishing cellular stress response profiles as biomarkers of homeodynamics, health and hormesis.
            (Demirovic and Rattan, 2013) Download
Aging is the progressive shrinkage of the homeodynamic space. A crucial component of the homeodynamic space is the stress response (SR), by virtue of which a living system senses disturbance and initiates a series of events for maintenance, repair, adaptation, remodeling and survival. Here we discuss the main intracellular SR pathways in human cells, and argue for the need to define and establish the immediate and delayed stress response profiles (SRP) during aging. Such SRP are required to be established at several age-points, which can be the molecular biomarkers of homeodynamic space and the health status of cells and organisms. SRP can also be useful for testing potential protectors and stimulators of homeodynamics, and can be a standard for monitoring the efficacy of potential pro-survival, health-promoting and aging-modulating conditions, food components and other compounds. An effective strategy, which makes use of SRP for achieving healthy aging and extending the healthspan, is that of strengthening the homeodynamics through repeated mild stress-induced hormesis by physical, biological and nutritional hormetins. Furthermore, SRP can also be the basis for defining health as a state of having adequate physical and mental independence of activities of daily living, by identifying a set of measurable parameters at the most fundamental level of biological organization.

Age-associated analysis of oxidative stress parameters in human plasma and erythrocytes.
            (Gil et al., 2006) Download
Oxidative damage accumulation in macromolecules has been considered as a cause of cellular damage and pathology. Rarely, the oxidative stress parameters in healthy humans related to the individual age have been reported. The purpose of this study was to examine the redox status in plasma and erythrocytes of healthy individuals and determine correlations between these parameters and the aging process. The following parameters were used: malondialdehyde (MDA), protein carbonyls (PCO), 4-hydroxy-2,3-trans-nonenal (HNE), reduced glutathione (GSH), glutathione disulfide (GSSG) and uric acid (UA) in blood and plasma samples of 194 healthy women and men of ages ranging from 18 to 84 years. The results indicate that the balance of oxidant and antioxidant systems in plasma shifts in favor of accelerated oxidation during ageing. That is demonstrated by increases of MDA, HNE, GSSG and by the slight decrease of erythrocytic GSH with age. As the content of UA is more determined by metabolic and nutritional influences than by the balance between prooxidants and antioxidants there was no significant age-related change observed. For plasma concentrations of HNE the first time age-dependent reference values for healthy humans are presented.

Platelet characteristics change with aging: role of estrogen receptor beta.
            (Jayachandran et al., 2005) Download
Estrogen receptor beta (betaER) is the predominant estrogen receptor in platelets. Experiments were designed to define phenotypic changes in platelets with aging following deletion of betaER (betaERKO). Blood was collected from wild-type and betaERKO female mice at 4-7 (young) and 24-25 (aged) months of age. In young animals, total number of platelets, number of platelets containing RNA (reticulated platelets), aggregation, dense body adenosine triphosphate secretion, and alpha granular secretion were the same in both groups. With aging, total number of platelets decreased but reticulated platelets increased in betaERKO mice; aggregation and dense granule adenosine triphosphate secretion decreased whereas basal expression of fibrinogen receptors increased with age in wild-type and betaERKO mice. Basal expression of P-selectin and annexin V binding increased with aging only in betaERKO mice; thrombin did not increase expression in these mice. Therefore, deletion of betaER is associated with specific platelet functions, which are expressed only with age-associated reproductive senescence.

Challenges and new opportunities for clinical nutrition interventions in the aged.
            (Johnson et al., 2011) Download
Nutritional status plays a critical role in the prevention and management of many chronic health conditions that are common in the elderly and are likely to become more prevalent as the population ages. This paper highlights several aspects of nutrition that require additional basic science and clinical application research to improve the health and well-being of older adults. Topics addressed are selected demographic and health indices, the uncertain benefits of energy restriction in aged humans compared with other species, the impact of food insecurity on health, the relationship between dietary protein and sarcopenia, the prevention and management of obesity while maintaining muscle mass and functional status, and controversy regarding high intakes of folic acid. Research needs regarding the safety, efficacy, and application of clinical interventions related to these topics also are discussed.

The role of insulin and IGF-1 signaling in longevity.
            (Katic and Kahn, 2005) Download
There are many theories of aging and parameters that influence lifespan, including genetic instability, telomerase activity and oxidative stress. The role of caloric restriction, metabolism and insulin and insulin-like growth factor-1 signaling in the process of aging is especially well conserved throughout evolution. These latter factors interact with each other, the former factors and histone deacetylases of the SIR family in a complex interaction to influence lifespan.

Rebuking the concept of ageing as a disease.
            (McCrory and Kenny, 2018) Download
It was with concern that we read the title of a recent Editorial1 in The Lancet Diabetes & Endocrinology entitled “Opening the door to treating ageing as a disease”. Although the purpose of the Editorial may have been to stimulate debate, we believe that any attempt to rebrand ageing as a disease is fundamentally misguided and retrograde. First, age is not a stable category but rather humans are part of different age cohorts throughout life. Second, rebranding ageing as a disease does nothing to further our understanding of the ageing process. Third, we feel the Editorial is in danger of confusing a risk factor for disease with a disease outcome. Finally, we feel that labeling ageing as a disease serves to reinforce ageist stereotypes and risks legitimizing insidious prejudice and discrimination of older people on the basis of age.

Estrogen, the ovary, and neutotransmitters: factors associated with aging.
            (Miller et al., 1998) Download
Our studies in the C57BL/6J mouse have been designed to examine the interactions of aging and the ovary, and their mutual effects on neuroendocrine function. In the pituitary, ovarian status and not age determines responsiveness to gonadotropin hormone releasing hormone (GnRH), but estrogen (E2) is an important mediator in CNS changes, and removal of the ovary (OVX) is deleterious to the neuroendocrine hypothalamus. OVX for just six days in young animals results in synaptic loss between noradrenergic terminals and gonadotropin hormone releasing hormone (GnRH) neurons. Long-term OVX, hypothesized to protect against neuroendocrine aging, fails to guard against any studied age-related changes. Some age-related changes occur as early as midlife. Although neuron number remains constant at middle age, opiatergic neurons undergo significant functional changes by producing opiate antagonist peptides. This change appears to be caused by alterations in the prohormone convertases, which cleave propeptide to peptide. Altered peptides may trigger the loss of reproductive capacity. The midlife shift in opiate peptide production is a component of natural developmental processes that begin in the neonate and continue through old age. In the cholinergic system, E2 mediates numbers of cholinergic receptors, cholinergic neurons, and cholinergic-modulated memory systems in both young and old animals. Regardless of age, ovarian steroids, if present at physiologic levels, are beneficial to the neuroendocrine CNS, and long-term deprivation from ovarian-produced factors is deleterious in the systems we have examined. Our studies have shown that deprivation from ovarian steroid hormones in the female appears to be a major factor in the health of the CNS and in events associated with aging.

Pomegranate vinegar beverage reduces visceral fat accumulation in association with AMPK activation in overweight women: A double-blind, randomized, and placebo-controlled trial
            (Park et al., 2014) Download
Abstract Recent studies on animals have suggested that vinegar consumption may confer an antiobesity effect through the activation of the AMP-activated protein kinase (AMPK) signaling pathway. However, mechanisms of action in humans remain largely unknown. A randomized, double-blind, placebo-controlled trial was performed to examine whether a pomegranate vinegar (PV) beverage alleviates adiposity in overweight subjects, with emphasis on AMPK activation. Seventy-eight overweight women (BMI ≥ 25) were randomly assigned to receive either PV (1.5 g acetic acid and 700 μg ellagic acid/200 mL/day) or a placebo for 8 weeks. The PV reduced visceral adipose tissue, as measured by computed tomography (P = 0.037), and enhanced AMPK phosphorylation (P = 0.013) compared with the placebo group. The PV tended to suppress downstream gene expression, such as that of sterol regulatory element binding protein-1c and acetyl coenzyme carboxylase, in adipose tissue. Together, these data suggest that PV is an excellent AMPK activator and may exert beneficial effects on adiposity.

The physiology of endocrine systems with ageing.
            (van den Beld et al., 2018) Download
During ageing, the secretory patterns of the hormones produced by the hypothalamic-pituitary axis change, as does the sensitivity of the axis to negative feedback by end hormones. Additionally, glucose homoeostasis tends towards disequilibrium with increasing age. Along with these endocrine alterations, a loss of bone and muscle mass and strength occurs, coupled with an increase in fat mass. In addition, ageing-induced effects are difficult to disentangle from the influence of other factors that are common in older people, such as chronic diseases, inflammation, and low nutritional status, all of which can also affect endocrine systems. Traditionally, the decrease in hormone activity during the ageing process has been considered to be detrimental because of the related decline in bodily functions. The concept of hormone replacement therapy was suggested as a therapeutic intervention to stop or reverse this decline. However, clearly some of these changes are a beneficial adaptation to ageing, whereas hormonal intervention often causes important adverse effects. In this paper, we discuss the effects of age on the different hypothalamic-pituitary-hormonal organ axes, as well as age-related changes in calcium and bone metabolism and glucose homoeostasis.

Testosterone treatment in older men: clinical implications and unresolved questions from the Testosterone Trials.
            (Yeap et al., 2018) Download
A decrease in the concentration of circulating testosterone in many older men is a biomarker and possibly a rectifiable contributing factor to ill health. Low circulating testosterone concentration has been associated with cardiovascular disease, reduced cognition, fracture risk, and anaemia. However, randomised placebo-controlled trials are essential to clarify the benefits and possible risks of testosterone treatment in men without hypothalamic, pituitary, or testicular disease. The Testosterone Trials (T-Trials) were a coordinated set of trials that, following a screening-to-enrolment ratio of 65:1, randomly assigned 790 men aged 65 years or older who had a baseline testosterone concentration of less than 9·54 nmol/L and symptoms consistent with hypogonadism, but no recognisable hypothalamic-pituitary-testicular axis pathology, to daily transdermal testosterone or placebo for 12 months. In the main trial, testosterone treatment resulted in a modest benefit for sexual function, whereas the other primary outcomes of vitality and physical function were not met. Data from concomitant substudies raised a possible concern over changes in coronary plaque volume, showed a neutral effect on memory and other cognitive functions, and revealed improvements in volumetric bone mineral density and anaemia. Although insufficient to alter the existing clinical equipoise, the T-Trials provided substantial new data on organ-specific outcomes for testosterone treatment in older men. Further clinical trials are necessary to determine whether testosterone treatment will translate into patient-valued health outcomes and to clarify effects on the cardiovascular system.

 


 

References

Anisimov, VN and A Bartke (2013), ‘The key role of growth hormone-insulin-IGF-1 signaling in aging and cancer.’, Crit Rev Oncol Hematol, 87 (3), 201-23. PubMed: 23434537
Balcerczyk, A, et al. (2014), ‘Enhanced antioxidant capacity and anti-ageing biomarkers after diet micronutrient supplementation.’, Molecules, 19 (9), 14794-808. PubMed: 25232703
Biessels, GJ, et al. (2002), ‘Ageing and diabetes: implications for brain function.’, Eur J Pharmacol, 441 (1-2), 1-14. PubMed: 12007915
Borumand, M and S Sibilla (2014), ‘Daily consumption of the collagen supplement Pure Gold Collagen(R) reduces visible signs of aging.’, Clin Interv Aging, 9 1747-58. PubMed: 25342893
Chaker, L, et al. (2018), ‘Clinical aspects of thyroid function during ageing.’, Lancet Diabetes Endocrinol, 6 (9), 733-42. PubMed: 30017801
Clegg, A and Z Hassan-Smith (2018), ‘Frailty and the endocrine system.’, Lancet Diabetes Endocrinol, 6 (9), 743-52. PubMed: 30017798
Collerton, J, et al. (2009), ‘Health and disease in 85 year olds: baseline findings from the Newcastle 85+ cohort study.’, BMJ, 339 b4904. PubMed: 20028777
Demirovic, D and SI Rattan (2013), ‘Establishing cellular stress response profiles as biomarkers of homeodynamics, health and hormesis.’, Exp Gerontol, 48 (1), 94-98. PubMed: 22525591
Gil, L, et al. (2006), ‘Age-associated analysis of oxidative stress parameters in human plasma and erythrocytes.’, Free Radic Res, 40 (5), 495-505. PubMed: 16551576
Jayachandran, M, et al. (2005), ‘Platelet characteristics change with aging: role of estrogen receptor beta.’, J Gerontol A Biol Sci Med Sci, 60 (7), 815-19. PubMed: 16079202
Johnson, MA, et al. (2011), ‘Challenges and new opportunities for clinical nutrition interventions in the aged.’, J Nutr, 141 (3), 535-41. PubMed: 21270372
Katic, M and CR Kahn (2005), ‘The role of insulin and IGF-1 signaling in longevity.’, Cell Mol Life Sci, 62 (3), 320-43. PubMed: 15723168
McCrory, C and RA Kenny (2018), ‘Rebuking the concept of ageing as a disease.’, Lancet Diabetes Endocrinol, 6 (10), 768. PubMed: 30266186
Miller, MM, et al. (1998), ‘Estrogen, the ovary, and neutotransmitters: factors associated with aging.’, Exp Gerontol, 33 (7-8), 729-57. PubMed: 9951619
Park, Ji Eun, et al. (2014), ‘Pomegranate vinegar beverage reduces visceral fat accumulation in association with AMPK activation in overweight women: A double-blind, randomized, and placebo-controlled trial’, Journal of Functional Foods, 8 (0), 274-81. PubMed:
van den Beld, AW, et al. (2018), ‘The physiology of endocrine systems with ageing.’, Lancet Diabetes Endocrinol, 6 (8), 647-58. PubMed: 30017799
Yeap, BB, ST Page, and M Grossmann (2018), ‘Testosterone treatment in older men: clinical implications and unresolved questions from the Testosterone Trials.’, Lancet Diabetes Endocrinol, 6 (8), 659-72. PubMed: 30017800