Impact of reduced insulin-like growth factor-1/insulin signaling on aging in mammals: novel findings

Growth hormone deficiency or resistance resulting from spontaneous or experimentally produced mutations in laboratory mice delay aging and increase lifespan. Alterations in insulin-like growth factor-1 (IGF-1) and insulin signaling emerged as likely mechanisms linking growth hormone and aging, and increased longevity was reported in mice with selective deletion of IGF-1 receptor in all tissues or insulin receptor in fat. Recent studies in mice with reduced IGF-1 levels or deletion of pregnancy-associated plasma protein-A, a protease that cleaves one of the IGF-1 binding proteins, strongly support the role of IGF-1 in the control of longevity. Reports of increased lifespan in mice with deletion of insulin receptor substrate (IRS) 1, reduced expression of IRS2, or selective deletion of IRS2 in the brain specifically implicate the IRS-PI3K-Akt-Foxo signaling pathway (which is shared by IGF-1 and insulin) in the control of aging. These important novel findings also strengthen the evidence for evolutionary conservation of mechanisms regulating lifespan in worms, insects and mammals.     

表观遗传调控健康衰老

衰老是自然界普遍存在的现象。衰老伴随着组织和器官功能的逐渐衰退,最终导致生物体死亡。衰老也是人们罹患老年性疾病如心血管疾病、神经退行性疾病、癌症、糖尿病等的主要风险因素。因此,延缓衰老对于预防和治疗衰老相关的疾病意义重大。衰老与遗传和表观遗传改变密切相关。最近,Nature杂志发表了中国科学院脑科学与智能技术卓越创新中心蔡时青研究组与中国科学院上海巴斯德研究所江陆斌研究组的合作成果。该研究发现了两个新的保守的表观调控因子妨碍健康衰老。     

TOR and ageing: a complex pathway for a complex process

Studies in invertebrate model organisms have led to a wealth of knowledge concerning the ageing process. But which of these discoveries will apply to ageing in humans? Recently, an assessment of the degree of conservation of ageing pathways between two of the leading invertebrate model organisms, Saccharomyces cerevisiae and Caenorhabditis elegans, was completed. The results (i) quantitatively indicated that pathways were conserved between evolutionarily disparate invertebrate species and (ii) emphasized the importance of the TOR kinase pathway in ageing. With recent findings that deletion of the mTOR substrate S6K1 or exposure of mice to the mTOR inhibitor rapamycin result in lifespan extension, mTOR signalling has become a major focus of ageing research. Here, we address downstream targets of mTOR signalling and their possible links to ageing. We also briefly cover other ageing genes identified by comparing worms and yeast, addressing the likelihood that their mammalian counterparts will affect longevity.     

Relationship of growth hormone and insulin-like growth factor-1 genotypes with growth and carcass traits in swine

The contribution of chromosomal regions linked to growth hormone (GH) and insulin-like growth factor-1 (IGF-1) loci to variation in preweaning average daily gain, postweaning average daily gain (ADG), 10th rib backfat, loin-eye area and muscle pH were evaluated. Offspring of four purebred sires (A–D; n = 150, 195, 148 and 136, respectively) and two crossbred sires (E and F; n = 157 and 145, respectively) were genotyped initially with GH and IGF-1 markers. When results of single marker analysis suggested possible linkage with a quantitative trait locus (QTL), additional flanking markers were typed for the family and interval mapping was performed. Growth hormone genotype was not associated with the traits evaluated in the study. Evidence suggestive of linkage was found for IGF-1 genotype and ADG in one sire family (lod = 2·3) where differences were 0.032 ± 0·01 kg/day for alternative sire alleles. Evidence for a putative ADG QTL was greatest in the interval between IGF-1 and Sw1071. A similar genomic region has been associated with growth variation in mice; however, QTL mapping precision in the current study is insufficient to establish similarity.     

Tyrannosaur ageing

Rate of ageing in tyrannosaurs was calculated from parameters of Weibull functions fitted to survival curves based on the estimated ages at death of fossilized remains. Although tyrannosaurs are more closely related to birds than to mammals, they apparently aged at rates similar to mammals of comparable size. Rate of growth in body mass of tyrannosaurs was similar to that of large mammals, and their rates of ageing were consistent with the estimated extrinsic mortality, which is strongly correlated with the rate of ageing across birds and mammals. Thus, tyrannosaurs appear to have had life histories resembling present-day large terrestrial mammals. Rate of ageing in warm-blooded vertebrates appears to be adjusted in response to extrinsic mortality and potential lifespan, independently of both physiological and developmental rates. However, individuals in species with the slowest rates of ageing suffer the highest proportion of ageing-related mortality, hence potentially strong selection to further postpone senescence. Thus, the longest observed lifespans in birds, tyrannosaurs and mammals might be close to the maximum possible.     

Design and synthesis of compounds that extend yeast replicative lifespan

This past decade has seen the identification of numerous conserved genes that extend lifespan in diverse species, yet the number of compounds that extend lifespan is relatively small. A class of compounds called STACs, which were identified as activators of Sir2/SIRT1 NAD+-dependent deacetylases, extend the lifespans of multiple species in a Sir2-dependent manner and can delay the onset of age-related diseases such as cancer, diabetes and neurodegeneration in model organisms. Plant-derived STACs such as fisetin and resveratrol have several liabilities, including poor stability and relatively low potency as SIRT1 activators. To develop improved STACs, stilbene derivatives with modifications at the 4' position of the B ring were synthesized using a Horner-Emmons-based synthetic route or by hydrolyzing deoxyrhapontin. Here, we describe synthetic STACs with lower toxicity toward human cells, and higher potency with respect to SIRT1 activation and lifespan extension in Saccharomyces cerevisiae. These studies show that it is possible to improve upon naturally occurring STACs based on a number of criteria including lifespan extension.     

pH neutralization protects against reduction in replicative lifespan following chronological aging in yeast

Chronological and replicative aging have been studied in yeast as alternative paradigms for post-mitotic and mitotic aging, respectively. It has been known for more than a decade that cells of the S288C background aged chronologically in rich medium have reduced replicative lifespan relative to chronologically young cells. Here we report replication of this observation in the diploid BY4743 strain background. We further show that the reduction in replicative lifespan from chronological aging is accelerated when cells are chronologically aged under standard conditions in synthetic complete medium rather than rich medium. The loss of replicative potential with chronological age is attenuated by buffering the pH of the chronological aging medium to 6.0, an intervention that we have previously shown can extend chronological lifespan. These data demonstrate that extracellular acidification of the culture medium can cause intracellular damage in the chronologically aging population that is asymmetrically segregated by the mother cell to limit subsequent replicative lifespan.     

Ageing and protein aggregation-mediated disorders: from invertebrates to mammals

Late onset is a common hallmark character of numerous disorders including human neurodegenerative maladies such as Huntington's, Parkinson's and Alzheimer's diseases. Why these diseases manifest in aged individuals and why distinct disorders share strikingly similar emergence patterns were until recently unsolved enigmas. During the past decade, invertebrate-based studies indicated that the insulin/IGF signalling pathway (IIS) mechanistically links neurodegenerative-associated toxic protein aggregation and ageing; yet, until recently it was unclear whether this link is conserved from invertebrates to mammals. Recent studies performed in Alzheimer's mouse models indicated that ageing alteration by IIS reduction slows the progression of Alzheimer's-like disease, protects the brain and mitigates the behavioural, pathological and biochemical impairments associated with the disease. Here, we review these novel studies and discuss the potential of ageing alteration as a therapeutic approach for the treatment of late onset neurodegeneration.     

pH neutralization protects against reduction in replicative lifespan following chronological aging in yeast

Chronological and replicative aging have been studied in yeast as alternative paradigms for post-mitotic and mitotic aging, respectively. It has been known for more than a decade that cells of the S288C background aged chronologically in rich medium have reduced replicative lifespan relative to chronologically young cells. Here we report replication of this observation in the diploid BY4743 strain background. We further show that the reduction in replicative lifespan from chronological aging is accelerated when cells are chronologically aged under standard conditions in synthetic complete medium rather than rich medium. The loss of replicative potential with chronological age is attenuated by buffering the pH of the chronological aging medium to 6.0, an intervention that we have previously shown can extend chronological lifespan. These data demonstrate that extracellular acidification of the culture medium can cause intracellular damage in the chronologically aging population that is asymmetrically segregated by the mother cell to limit subsequent replicative lifespan.     

Growth hormone signaling is necessary for lifespan extension by dietary methionine

Growth hormone significantly impacts lifespan in mammals. Mouse longevity is extended when growth hormone (GH) signaling is interrupted but markedly shortened with high‐plasma hormone levels. Methionine metabolism is enhanced in growth hormone deficiency, for example, in the Ames dwarf, but suppressed in GH transgenic mice. Methionine intake affects also lifespan, and thus, GH mutant mice and respective wild‐type littermates were fed 0.16%, 0.43%, or 1.3% methionine to evaluate the interaction between hormone status and methionine. All wild‐type and GH transgenic mice lived longer when fed 0.16% methionine but not when fed higher levels. In contrast, animals without growth hormone signaling due to hormone deficiency or resistance did not respond to altered levels of methionine in terms of lifespan, body weight, or food consumption. Taken together, our results suggest that the presence of growth hormone is necessary to sense dietary methionine changes, thus strongly linking growth and lifespan to amino acid availability.     

Embryo development and ageing in birds and mammals

The rate of ageing is a genetically influenced feature of an individual's life history that responds to selection on lifespan. Various costs presumably constrain the evolution of prolonged life, but these have not been well characterized and their general nature is unclear. The analyses presented here demonstrate a correlation among birds and mammals between rates of embryonic growth and ageing-related mortality, which are quantified by the exponents of fitted power functions. This relationship suggests that rapid early development leads to accelerated ageing, presumably by influencing some aspect of the quality of the adult individual. Although the mechanisms linking embryo growth rate and ageing are not known, a simple model of life-history optimization shows that the benefits of longer life can be balanced by connected costs of extended development.     

Information theory and the neuropeptidergic regulation of seasonal reproduction in mammals and birds

Seasonal breeding in the temperate zone is a dramatic example of a naturally occurring change in physiology and behaviour. Cues that predict periods of environmental amelioration favourable for breeding must be processed by the brain so that the appropriate responses in reproductive physiology can be implemented. The neural integration of several environmental cues converges on discrete hypothalamic neurons in order to regulate reproductive physiology. Gonadotrophin-releasing hormone-1 (GnRH1) and Kisspeptin (Kiss1) neurons in avian and mammalian species, respectively, show marked variation in expression that is positively associated with breeding state. We applied the constancy/contingency model of predictability to investigate how GnRH1 and Kiss1 integrate different environmental cues to regulate reproduction. We show that variation in GnRH1 from a highly seasonal avian species exhibits a predictive change that is primarily based on contingency information. Opportunistic species have low measures of predictability and exhibit a greater contribution of constancy information that is sex-dependent. In hamsters, Kiss1 exhibited a predictive change in expression that was predominantly contingency information and is anatomically localized. The model applied here provides a framework for studies geared towards determining the impact of variation in climate patterns to reproductive success in vertebrate species.