Biogerontology

Understanding how we can age healthily is a challenge at the heart of biogerontological interest. Whereas myriad genes are known to affect the lifespan of model organisms, effects of such interventions on healthspan—the period of life where an animal is considered healthy, rather than merely alive—are less clear. To understand relationships between life- and healthspan, in recent years several platforms were developed with the purpose of assessing both readouts simultaneously. We here relied on one such platform, the WorMotel, to study effects of adulthood-restricted knock-down of 130 Caenorhabditis elegans genes on the locomotive health of the animals along their lifespans. We found that knock-down of six genes affected healthspan while lifespan remained unchanged. For two of these, F26A3.4 and chn-1, knock-down resulted in an improvement of healthspan. In follow-up experiments we showed that knockdown of F26A3.4 indeed improves locomotive health and muscle structure at old age.

The results of previous experimental studies of effects of antidiabetic biguanides (phenformin and buformin) on life span and spontaneous tumor incidence in mice and rats were recalculated and reanalyzed using standard demographic models of mortality. The chronic treatment of female C3H/Sn mice with phenformin prolonged the mean life span by 21.1% (P < 0.05), the mean life span of the last 10%survivors by 28.4% and the maximum life span by 5.5 months (by 26%) in comparison with the control. The demographic aging rate represented by the estimate of respective Gompertz's parameter decreased by 31.2% and MRDT increased 1.45-fold. The treatment significantly inhibited (4.0-fold, P < 0.01) the incidence of mammary adenocarcinomas in mice. Administration of phenformin to female LIO rats failed to influence the mean lifespan. At the same time, the mean life span of the last 10% survivors increased by 10.1% (P < 0.05), and maximum life span increased by 3 months (+9.8%). Phenformin attenuated the development of spontaneous tumors in comparison to the control. The treatment of female rats with another antidiabetic biguanide, buformin, slightly increased their mean life span (by 7.3%; P > 0.05). The mean life span of the last 10%survivors increased by 12% (P < 0.05) and the maximum life span increased by 2 months (+5.5%) as compared with controls. The population aging rate decreased by 18.1% (P < 0.05) and MRDT increased 1.22-foldunder the influence of buformin (P < 0.05). The total tumor incidence decreased by 49.5%in buformin-treated rats. Both antidiabetic biguanides slightly decreased the body weight, slowed down the age-related decline of there productive function in female rats. The results of our experiments provide evidence that antidiabetic biguanides are promising geroprotectors as well as drugs which can be used in the prevention of cancer.

The vascular endothelium is a protective barrier between the bloodstream and the vasculature that may be disrupted by different factors such as the presence of diseased states. Diseases like diabetes and obesity pose a great risk toward endothelial cell inflammation and oxidative stress, leading to endothelial cell dysfunction and thereby cardiovascular complications such as atherosclerosis. Sirtuins are NAD+-dependent histone deacetylases that are implicated in the pathophysiology of cardiovascular diseases, and they have been identified to be important regulators of endothelial cell function. A handful of recent studies suggest that disbalance in the regulation of endothelial sirtuins, mainly sirtuin 1 (SIRT1), contributes to endothelial cell dysfunction. Herein, we summarize how SIRT1 and other sirtuins may contribute to endothelial cell function and how presence of diseased conditions may alter their expressions to cause endothelial dysfunction. Moreover, we discuss how the beneficial effects of exercise on the endothelium are dependent on SIRT1. These mainly include regulation of signaling pathways related to endothelial nitric oxide synthase phosphorylation and nitric oxide production, mitochondrial biogenesis and mitochondria-mediated apoptotic pathways, oxidative stress and inflammatory pathways. Sirtuins as modulators of the adverse conditions in the endothelium hold a promising therapeutic potential for health conditions related to endothelial dysfunction and vascular ageing.

Estrogen compounds have been described as important brain protectors. This study investigated the effects of estradiol valerate (EV—0.3 mg/kg) and two concentrations of tibolone (TB1 = 0.5 mg/kg and TB2 = 1 mg/kg) on brain oxidative stress parameters and blood biochemistry in ovariectomized female rats, of three different age groups (young—2 months, adult—8 months, and old—20 months). In the brain cortex, young and old TB2-treated and old no-hormone-replacement (NR) females showed lower lipid hydroperoxide (LPO) levels compared to young Sham and adult TB1 animals (P < 0.05). Also in the cortex, both tibolone doses produced higher (P < 0.05) total antioxidant capacity (TOSC) levels compared to EV-treated adult females. Ovariectomized adult females (NR, EV, TB1 and TB2) showed lower (P < 0.05) TOSC levels in the hippocampus compared to the Sham control. Reactive oxygen species (ROS) were higher (P < 0.05) in old females compared to all younger ones. TB2-treated adults showed higher plasma glucose (P < 0.05) levels compared to old animals. Regardless of age, TB2 treatment increased female (P < 0.05) LDL levels compared to Sham and EV-treated animals. In old females, TB2 significantly increased HDL levels compared to Sham controls, and decreased triglyceride levels were shown in EV, TB1 and TB2 compared to Sham old females. The Atherogenic Index of Plasma was higher (P < 0.05) in adult tibolone-treated females compared to both young and old TB2-treated females. These results suggest that the effects of gonad steroid on brain and blood physiology change significantly with aging, and that evaluating hormonal treatment types and doses could be the key factor in the potential use of a specific hormone therapy.

The senescence- accelerated mouse prone 8 (SAMP8) is a well- characterized animal model of senescence that shows early age- related neurodegeneration with impairment in learning and memory skills when compared with control senescence- resistant mice (SAMR1). In the current study, we investigated whether such impairment could be partly due to changes in mitochondrial DNA (mtDNA) repair capacity and mitochondrial DNA damage in the brain of SAMP8 mice. Besides we studied whether these potential changes were related to modifications in two major processes likely involved in aging and neurodegeneration: apoptosis and inflammation. We observed that the specific activity of one of the main mtDNA repair enzymes, the mitochondrial APE1, showed an age- related reduction in SAMP8 animals, while in SAMR1 mice mitochondrial APE1 increased with age. The reduction in mtAPE1 activity in SAMP8 animals was associated with increased levels of the DNA oxidative damage marker 8oxodG in mtDNA. Our results also indicate that these changes were related to a premature increase in apoptotic events and inflammation in the brain of SAMP8 mice when compared to SAMR1 counterparts. We suggest that the premature neurodegenerative phenotype observed in SAMP8 animals might be due, at least in part, to changes in the processing of mtDNA oxidative damage, which would lead to enhancement of apoptotic and inflammatory processes.

Changes in the endocrine system have been suggested to act as signaling factors in the regulation of age-related events. Among the different hormones that have been linked to the aging process, estrogens have been widely investigated. They have been associated with inflammatory and oxidative processes and several investigations have established a relationship between the protective effects of estrogens and the mitochondrial function. Mitochondrial DNA is subjected to continuous oxidative attack by free radicals, and the base excision repair (BER) pathway is the main DNA repair route present in mitochondria. We have investigated the effect of estrogen levels on some of the key enzymes of BER in brain and liver mitochondria. In both tissues, depletion of estrogens led to an increased mitochondrial AP endonuclease (mtAPE1) activity, while restoration of estrogen levels by exogenous supplementation resulted in restitution of control APE1 activity only in liver. Moreover, in hepatic mitochondria, changes in estrogen levels affected the processing of oxidative lesions but not deaminations. Our results suggest that changes in mtAPE1 activity are related to specific translocation of the enzyme from the cytosol into the mitochondria probably due to oxidative stress changes as a consequence of changes in estrogen levels.

Molecular chaperones are abundant, well-conservedproteins responsible for the maintenance of theconformational homeostasis of cellular proteins andRNAs. Environmental stress is a proteotoxic insult tothe cell, which leads to chaperone (heat shockprotein, stress protein) induction. The protectiverole of chaperones is a key factor for cell survivaland in repairing cellular damage. The present reviewsummarizes our current knowledge about changes inchaperone expression and function in the agingprocess, as well as their possible involvement in thedevelopment of longevity and cellular senescence. Wealso overview their putative role in neurodegenerativediseases, such as in Alzheimer's disease and thechanges in immune and autoimmune response againstvarious chaperones in aging.

Phần lớn các nghiên cứu về tác động của độ tuổi lên quá trình lành vết thương trên da (WH) đều so sánh những con vật già với những con vật trẻ. Tuổi trung niên thường bị bỏ qua trong nghiên cứu sinh lão học mặc dù nhiều chức năng suy giảm theo độ tuổi bắt đầu từ giữa độ tuổi trung niên. Với lý do này, chúng tôi đã nghiên cứu các mẫu biểu hiện gen trong quá trình lành vết thương trên da ở những con chuột đực tuổi trung niên muộn so với những con chuột đực trưởng thành trẻ tuổi, sử dụng các mô hình lấy mẫu đầu và lưng. Lý do đằng sau nghiên cứu này là tác động của độ tuổi sẽ được phát hiện đầu tiên ở mức độ phiên mã. Chúng tôi đã xác định một số con đường mà ở đó có sự gia tăng hoạt động quá mức ở những con chuột trung niên, cả trong da nguyên vẹn lẫn trong quá trình lành vết thương. Trong số đó có nhiều con đường trao đổi chất, viêm miễn dịch và thúc đẩy sự tăng trưởng. Những thay đổi phiên mã này rõ ràng hơn nhiều ở vùng đầu so với vùng lưng. Tóm lại, tuổi trung niên có ảnh hưởng đáng kể đến biểu hiện gen trong da nguyên vẹn và đang lành. Có vẻ như mô hình lấy mẫu ở đầu nhạy cảm hơn với tác động của độ tuổi so với mô hình lưng, và chúng tôi đề xuất rằng nó nên được áp dụng rộng rãi hơn trong nghiên cứu lão hóa về lành vết thương.

The trade-off between reproduction and somatic maintenance is one of the most studied concepts of modern evolutionary ecology. This theory predicts a negative relationship between maximum species longevity and total reproductive output. However, studies performed on natural animal populations have found contradictory results, probably due to the unlikelihood of wild animals gaining both maximum longevity and maximum potential fecundity. A comparison of the mortality rates and reproductive output of four ecologically distinct rodent species of Cricetidae family that were maintained in the laboratory in controlled conditions revealed the different life-history tactics of subterranean social mole voles and three related aboveground species: hydrophilic water voles, arid dwarf hamsters and steppe lemmings. Regardless of the relatively higher mortality rates at early ages in mole voles, this species has considerably higher maximum species longevity and smaller litter sizes that do not depend on calendar age, whereas in dwarf hamsters and water voles clear negative correlations between female age and litter size were detected. Steppe lemmings, as a semi-social arid species, shared some life-history tactics with both mole voles and aboveground non-social rodents.

During reproductive aging female rats enter an anovulatory state of persistent estrus (PE). In an animal model of re-instatement of estrus cyclicity in middle-aged PE rats we injected the animals with progesterone (0.5 mg progesterone/kg body weight) at 12:00 for 4 days whereas control animals received corn oil injections. After the last injection animals were analyzed at 13:00 and 17:00. Young regular cycling rats served as positive controls and were assessed at 13:00 and 17:00 on proestrus. Progesterone treatment of middle-aged PE rats led to occurrence of luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin surges in a subset of animals that were denoted as responders. Responding middle-aged rats displayed a reduction of ER-β mRNA in the preoptic area which was similar to the effect in young rats. Within the mediobasal hypothalamus, only young rats showed a decline of ER-α mRNA expression. A decrease of ER-α mRNA levels in the pituitary was observed in progesterone-responsive rats and in young animals. ER-β mRNA expression was reduced in young regular cycling rats. ER-β mRNA levels in the ovary were reduced following progesterone treatment in PE rats and in young rats. Taken together our data show that cyclic administration of progesterone reinstates ovulatory cycles in intact aging females which have already lost their ability to display spontaneous cyclicity. This treatment leads to the occurrence of preovulatory LH, FSH and prolactin surges which are accompanied by differential modulation of ERs in the hypothalamus, the pituitary and the ovary.