Search tips
Search criteria 


Logo of transbThe Royal Society PublishingPhilosophical Transactions BAboutBrowse By SubjectAlertsFree Trial
Philos Trans R Soc Lond B Biol Sci. 2011 January 12; 366(1561): 99–107.
PMCID: PMC3001304

Mammalian models of extended healthy lifespan


Over the last two centuries, there has been a significant increase in average lifespan expectancy in the developed world. One unambiguous clinical implication of getting older is the risk of experiencing age-related diseases including various cancers, dementia, type-2 diabetes, cataracts and osteoporosis. Historically, the ageing process and its consequences were thought to be intractable. However, over the last two decades or so, a wealth of empirical data has been generated which demonstrates that longevity in model organisms can be extended through the manipulation of individual genes. In particular, many pathological conditions associated with the ageing process in model organisms, and importantly conserved from nematodes to humans, are attenuated in long-lived genetic mutants. For example, several long-lived genetic mouse models show attenuation in age-related cognitive decline, adiposity, cancer and glucose intolerance. Therefore, these long-lived mice enjoy a longer period without suffering the various sequelae of ageing. The greatest challenge in the biology of ageing is to now identify the mechanisms underlying increased healthy lifespan in these model organisms. Given that the elderly are making up an increasingly greater proportion of society, this focused approach in model organisms should help identify tractable interventions that can ultimately be translated to humans.

Keywords: insulin signalling, ageing, nutrient sensing, target of rapamycin

1. Introduction

The last 200 years has seen an astonishing increase in human life expectancy in the developed world, with an estimated 30 years added to average life expectancy since the turn of the twentieth century [1]. This increase has been achieved through factors including better diet, cleaner water and significantly improved preventative medicine and palliative care [2]. The elderly are therefore making up a significantly greater proportion of the population, particularly when allied to low fertility and immigration [1]. Recent projections suggest that approximately 1.6 per cent of the UK population, compared with the current approximately 0.7 per cent, will be over 90 years of age by 2020 [3]. This means that if current trends continue, then the majority of babies born in the UK since 2000 will celebrate their 100th birthday [1]. These rapidly altering demographic profiles will have enormous social, economic and ethical implications because ageing is inexorably linked to physiological decline, loss of independence and decreased quality of life [4]. In particular, the prevalence of cardiovascular disease, dementia, cancer, sarcopaenia, osteoporosis, osteoarthritis and type-2 diabetes all increase significantly with advancing age [46].

Obvious practical, ethical and economic obstacles exist to longitudinal studies investigating the determinants of human lifespan. Therefore, much effort in the biology of ageing has employed model organisms like yeast, the nematode worm Caenorhabditis elegans, the fruitfly Drosophila melanogaster and the mouse [2,79]. While it has been established for over 70 years that dietary restriction (DR) extends lifespan in many organisms [1012], it has only been more recently that ageing and lifespan have been shown to be modulated by genetic factors [2,1315]. Furthermore, many age-related pathophysiological processes relevant to the diseases of ageing in humans can be modelled in such organisms.

Specific mutations in the insulin/insulin-like growth factor (IGF) signalling (IIS) pathway extend lifespan in model organisms [79,13,1619]. Polymorphisms in several IIS and growth hormone (GH)-related genes correlate with human longevity [2022], and attenuated IIS may underlie the long life of GH/GH receptor-deficient dwarf mice (e.g. Ames (Prop1df/df), Snell (Pit1dw/dw), Little (Ghrhrlit/lit), growth hormone receptor knockout (GHR-KO) [23]). The target of rapamycin (TOR) pathway also plays a key and conserved role in longevity control [2429]. It is clear that understanding how exactly the IIS, GH and mTOR signalling pathways interact with one another to increase lifespan and healthspan is a key challenge to future research.

The primary objective of biology of ageing research is to identify what underpins ageing in order to generate interventions that attenuate age-related pathology and consequently improve healthy lifespan in humans. Therefore, model organism studies that show both extended lifespan and improved health over this long life are crucial if we hope to achieve this. This review will therefore examine those studies of genetically modified mice demonstrating evidence of extended healthy lifespan through the positive effects on age-sensitive biomarkers and/or resistance to age-related pathology (table 1). Our approach is to describe in turn the various pathophysiological processes and diseases relevant to ageing in humans that are ameliorated in long-lived genetic mice. However, it should be noted that in many cases a limited number of pathologies have been examined, with relatively few long-lived mutants having undergone detailed examination in a broad range of disease parameters.

Table 1.
Attenuated ageing-related decline in various phenotypic parameters in genetic mouse models of healthy ageing. (Long-lived genetic model and primary reference. 1, Homozygous ribosomal protein S6 kinase 1 knockout [29]; 2, homozygous insulin receptor substrate ...

2. Mutations in individual genes that extend healthy lifespan in mammals

(a) Maintenance of a youthful metabolic profile in long-lived mice

Ageing in humans is associated with greater adiposity, particularly visceral fat, higher body mass index and a significant loss in lean mass [3032]. Commonly associated with these age-related changes in body composition are impairments in glucose tolerance and insulin sensitivity. Elevated adiposity and insulin resistance are significant risk factors for type-2 diabetes, coronary heart disease and stroke. In addition, insulin resistance is linked to higher colon, liver and pancreatic cancer incidence [33], more aggressive breast cancer tumours [34] and Alzheimer's disease (AD) development [35].

The most widely studied phenotypic parameters in long-lived mice are those associated with body composition and glucose/insulin homeostasis. It is well established that long-lived GH/GH receptor dwarf mice are highly insulin sensitive [3638]. Indeed, the absence of lifespan extension in GHR-KO mice following DR [36] or intermittent fasting [39] is suggested to be because these dietary interventions cannot further increase insulin sensitivity in these animals [40]. However, long-lived Snell dwarf mice are obese and hyperleptinaemic in old age [41], and have unaltered fasting (3–6 h) insulin and glucose levels relative to control mice at 20–23 months of age [41,42]. Percentage fat mass, normalized to total body mass, was also elevated in GHR-KO mice over a 2 year period relative to controls, with the increased adiposity more apparent in males [43].

Long-lived fat-specific insulin receptor knockout (FIRKO) mice are lean, have reduced total-body triglyceride levels and show resistance to age-related deterioration in glucose tolerance compared with wild-type (WT) controls [16]. Insulin receptor substrates 1 and 2 are key intracellular effectors of the IIS receptors [19]. Mice heterozygote for insulin receptor substrate 2 (Irs2+/−) have been described as long-lived in one study [44], but not in another despite using the same mouse model [45]. Nonetheless, both male and female Irs2+/− mice were significantly more insulin sensitive at approximately 22 months of age relative to controls in the earlier study, despite no differences observed between genotypes at two months of age [44]. Reportedly, long-lived female mice heterozygote for the IGF-1 receptor (Igf1r+/−) ( [46], but see also [47]) are also slightly more glucose tolerant compared with control animals [46]. Recently, we have shown that 600-day-old female mice null for ribosomal protein S6 kinase 1 (S6K1−/−), a downstream effector of mTOR signalling and IIS, are lean, hypoleptinaemic, glucose tolerant and insulin sensitive (assessed by the updated homeostasis model, HOMA2; [29]). These improvements are despite S6K1−/− mice being glucose intolerant at eight weeks of age [29].

Mice null for RIIβ, a regulatory subunit of protein kinase A, are long-lived, and resistant to both age-related obesity and hyperleptinaemia [48]. These mice also have lower fasting blood glucose levels at 24 months of age compared with WT littermates [48]. Male RIIβ mutants were more insulin sensitive at young (two to five months) and old (18 months) ages relative to controls, although young females were not [48]. Studies examining the role of the cellular reverse transcriptase telomerase (TERT) during ageing have been complicated by the cancer-promoting effects of telomerase [49]. However, over-expression of Tert in the background of enhanced cancer resistance (enhanced expression of p53, p16 and p19ARF) increased lifespan in Sp53/Sp16/SArf/TgTert transgenic mice [50]. These animals were also protected against age-related deteriorations in glucose tolerance between 30 and 76 weeks of age [50].

However, several other studies demonstrate that insulin sensitivity per se is not a prerequisite for a long and healthy lifespan. For example, long-lived female insulin receptor substrate 1 null (Irs1−/−) mice are both insulin and IGF-1 resistant at 450 days of age [19]. However, remarkably, these animals are protected against an age-related deterioration in glucose tolerance seen in WT animals because of lifelong beta-cell compensation and associated hyperinsulinaemia [19]. It should also be noted that despite this insulin-resistant phenotype, Irs1−/− mice are lean and hypoleptinaemic at 450 days and 700 days of age [19]. Long-lived heterozygote brain-specific IGF-1 receptor knockout mice (bIGF1RKO+/−) had greater adiposity, hyperleptinaemia and impaired glucose tolerance at 10 months of age compared with WT mice [18]. Insulin resistance and glucose intolerance were also observed in long-lived brain-specific IRS2 heterozygote and homozygote (bIrs2+/−, bIrs2−/−) mice [44]. Finally, mice with over-expression of Klotho, a single-pass transmembrane protein, are long-lived but insulin and IGF-1 resistant [51].

(b) Preserved cognitive and motor functions in long-lived mice

Age itself is the greatest risk factor for cognitive decline and dementia [5]. Brain-related pathologies will have increasingly important implications to healthcare, governmental policy and society, given that recent estimates predict that AD cases in the USA alone will rise from 377 000 cases in 1995 to around one million by 2050 [52].

Undoubtedly, the best studied long-lived mice with regard to cognitive function and ageing are the GH/GH receptor dwarfs, with several studies indicating preserved cognitive function in these mice at old age [5355]. For example, old (17–20 months) GHR-KO and Ames mice (19–21 months) had improved learning and memory compared with age-matched WT controls [54,55]. Exactly why this is the case is currently unknown, but intriguingly Ames mice have been shown to have increased hippocampal neurogenesis in adulthood [56,57].

Several other studies suggest that delayed age-related cognitive decline exists in long-lived mice. For example, female Irs1−/− mice at 450 days of age showed better motor/neurological function, as assessed by forced motor activity performance on a rotating rod (rotarod) apparatus, compared with WT mice [19]. Importantly, no improvement was seen in young (80-day-old) Irs1−/− mice, suggesting that the better rotarod performance in old age was not due to the dwarf phenotype. An enhancement in rotarod performance was also demonstrated in female S6K1−/− mice at 600 days of age [29]. In addition, these mice had enhanced overall general activity and exploratory drive performance during open-field testing at this age [29]. Sp53/Sp16/SArf/TgTert mice at approximately 12 months of age also demonstrated better neuromuscular coordination during a tightrope test [50], and bIrs2+/− and bIrs2−/− mice were significantly more active than controls at 22 months of age [44].

Long-lived mice also appear more resistant to the sequelae of neurodegenerative conditions such as AD. For example, hippocampal slices from adult Ames mice are significantly more resistant to β-amyloid (Aβ) toxicity compared with controls [58]. AD is associated with altered neuronal insulin signalling [59], and several studies have investigated the effect of altered insulin signalling on AD progression. Mice expressing the Swedish mutation of amyloid precursor protein (APPSW, Tg2576) and crossed with long-lived bIGF1RKO+/− mice [18] were rescued from APPSW-induced early mortality and had significantly reduced Aβ accumulation at 60 weeks of age [59]. In addition, global IRS-2 deficiency in this AD model completely reversed early mortality and delayed Aβ accumulation [59]. In agreement, global IRS2 deficiency in APPSW mice ameliorated Aβ pathology and improved several behavioural parameters despite increasing tau phosphorylation [60]. Interestingly, this is despite Irs2−/− mice of both sexes being significantly short-lived [19]. Mice expressing two AD-linked transgenes and crossed with Igf1r+/− mice [46] were protected against several AD-related pathologies and impaired cognitive function [61]. Rapamycin, an inhibitor of the mTOR pathway, treatment significantly increases lifespan in mice [25] and was recently shown to attenuate cognitive deficits, Aβ pathology and tau pathology in two different AD mouse models [62,63].

(c) Delayed bone loss in long-lived mice

Osteoporosis, which clinically presents as reduced bone mass and altered bone structure, is a significant public health issue. For example, osteoporosis-related fractures, particularly hip fractures, are a major cause of morbidity and mortality in humans [64]. Clinical studies also suggest that there is overlap between several common disease mechanisms underlying osteoporosis and cardiovascular disease, including chronic inflammation, insulin resistance and obesity [65].

Mice also are prone to significant losses in bone volume with advancing age (e.g. [66]). Several studies examining long-lived mice have used a cross-sectional approach to show simultaneous preservation of bone function and quality with age. We have demonstrated, using micro-computed tomography, that female Irs1−/− mice at 450 and 700 days of age are resistant to age-related bone dysfunction [19]. Irs1−/− mice had greater cancellous bone volume, increased trabecular number and reduced trabecular separation compared with age-matched controls. Interestingly, this preservation in bone quality during ageing was seen despite young Irs1−/− mice being osteopenic [67]. Furthermore, using the same methodology, we recently showed that 600-day-old female S6K1−/− mice also had greater tibial bone volume and trabecular number compared with age-matched WT controls [29]. A preservation in bone volume with age was also reported in mice lacking type 5 adenylyl cyclase (AC5 KO), a key catalytic enzyme in the synthesis of cyclic adenosine monophosphate from adenosine triphosphate [68]. Female AC5 KO mice at 23 months of age had greater femoral bone density and calcification, less evidence of healing stress fractures and improved bone strength compared with controls [68]. Interestingly, tail tendons from young (four to eight months) and old (16–19 months) Snell mice are more resistant to urea-induced collagen denaturing, and Snell mice are protected against articular ageing and osteoarthritis [41,69]. Preservation of skeletal function during ageing is therefore often seen in long-lived mouse models.

(d) Attenuated visual deterioration in long-lived mice

Visual impairment and visual loss caused by several pathologies including macular degeneration, glaucoma and cataracts increase significantly in humans with advancing age [70]. These visual impairments may also exacerbate additional age-related pathologies including metabolic dysfunction, cardiovascular disease, insomnia, depression and impaired cognition through disruption in circadian photoreception [71].

Mice show comparable age-related increases in cataracts to humans, with similar regions of the lens affected. For example, C57BL/6 mice display a highly significant increase in the degree of cataract severity between six and 28 months of age [72]. Using a slit lamp protocol, it has been shown that both GHR-KO mice [72] and Snell dwarf mice [73] are resistant to age-related cataracts, with no differences in cataract levels relative to WT controls reported in GHR-KO mice at six months of age [72]. However, delayed cataract formation does not appear to be universal among long-lived mutant mice, as no difference was reported between long-lived glutathione peroxidase 4 heterozygous knockout mice (Gpx4+/−) and controls at 25 months of age [74].

(e) Improved cardiac function in long-lived mice

Cardiovascular disease is a primary cause of mortality in humans worldwide, with its risk increasing significantly with advancing age [75]. Cardiovascular disease per se is not thought to be a prominent cause of mortality in most laboratory mouse strains. However, many of the age-related deteriorations in cardiovascular function observed in humans are also observed in mice [76]. Consequently, there is good evidence that aspects of cardiovascular ageing are significantly attenuated in long-lived mice.

It has been demonstrated that AC5 KO mice, for example, are resistant to age-related myocardial fibrosis and left ventricular (LV) hypertrophy [68]. These mice also have reduced cardiac apoptosis and smaller myocyte cross-sectional area at 20–30 months of age compared with WT mice. Male RIIβ null mice have preserved cardiac function and less evidence of LV hypertrophy at 24 months of age [48]. Long-lived mice over-expressing human catalase within their mitochondria (MCAT mice) [77] were also highly resistant to a range of cardiac-associated pathologies, including arteriosclerosis, cardiomyopathy, impaired diastolic function and LV hypertrophy at 20–25 months of age [76,77]. Interestingly, age-dependent cardiomyopathy in mice carrying a homozygous mutation in the exonuclease-encoding domain of mitochondrial polymerase gamma (Polgm/m mice) was ameliorated when Polgm/m mice were crossed with MCAT mice [78]. Transgenic mice over-expressing human metallothionein-IIa, a heavy metal-binding antioxidant, in cardiac tissue are long-lived and protected against both age-related diastolic dysfunction and decreased cardiac contractile reserve capacity [79]. Long-lived mice null for the cytoplasmic adaptor protein p66shc (p66shc−/−) are long-lived [80] and resistant to age-dependent reactive oxygen species-mediated endothelial dysfunction [81]. p66shc−/− mice were protected against angiotensin II-induced LV hypertrophy, associated cardiomyocyte and endothelial cell apoptosis [82]. Long-lived mice null for either pregnancy-associated plasma protein A (PAPP-A-KO) [83], a metalloproteinase that degrades IGF-binding proteins, or p66shc [84] are protected against high fat diet-induced atherosclerosis when maintained in an apolipoprotein E-deficient (ApoE) background.

(f) Protection against cancer in long-lived mice

Many cancers, including breast, prostate and colorectal, increase with advancing age, with the vast majority of cancer cases seen in people over 60 years of age [85]. The risk of mortality from cancer also increases in an age-dependent manner [85,86], although both incidence and mortality rate apparently plateau and subsequently decline after 90 years of age [86]. Cancer is the primary cause of death in most mouse strains, although tumour type appears highly strain specific [87]. For example, the C57BL/6 strain commonly used in ageing research is particularly prone to lymphosarcoma [74,88]. Significant effort has focused on whether interventions that extend lifespan impact on cancer incidence and progression, with most studies examining end of life pathology.

Several studies have investigated whether long-lived GH/GH receptor-deficient dwarf mice are protected against cancer [89,90]. In Ames dwarfs, age-related neoplastic disease was delayed and adenocarcinoma severity reduced despite the percentage of tumour-bearing mice at death being similar to WT mice [91]. However, tumour burden (the number of different tumours) in Ames mice was similar to controls [91]. In contrast, Snell dwarfs had significantly reduced age-related tumour burdens [89] and a non-significant trend (p = 0.06) for reduced lymphoma and mammary adenocarcinoma [73]. GHR-KO mice also had decreased tumour incidence, reduced tumour burden, less severe pulmonary adenocarcinomas and an age-related delay in fatal neoplastic diseases relative to controls [92].

A comprehensive examination by two pathologists reported that a similar percentage of Gpx4+/− and control mice (55–60%) had neoplastic disease, although an age-related delay in fatal lymphoma was seen in Gpx4+/− mice [74]. Gross pathological investigation of 23- to 28-month-old PAPP-A-KO mice revealed significantly reduced tumour burden and no evidence of multiple tumours unlike control mice [93]. RIIβ−/− null mice had less lymphosarcoma and splenic tumours compared with controls, although no differences were observed in hepatic tumours [48]. MCAT mice had unaltered haematopoietic tumour incidence compared with WT controls, but a significant reduction in the severity and tumour burden of non-haematopoietic tumours was seen post-mortem [88]. Mice null for the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF-KO) showed less evidence of hemangiosarcomas compared with WT controls [94]. However, we observed no difference in macroscopic tumour incidence at death in female S6K1−/− compared with controls [29], in agreement with findings in bIGF1RKO+/− mice [18]. Lifespan extension following rapamycin treatment in mice also did not alter the distribution in the presumptive causes of mortality in mice, including tumour incidence [25].

(g) Youthful immune profile and reduced inflammation in long-lived mice

The presence of a chronic inflammatory state in humans, e.g. elevated pro-inflammatory cytokines and local infiltration of assorted inflammatory cells, underlies several ageing-related diseases, including cancer [6,86]. In mice, alterations in T-cell populations (i.e. greater proportion of naive T cells relative to memory T cells) are predictive of both a resistance to various cancers [95] and longevity [96,97]. However, it should be noted that this assay may not specifically indicate improved immune function (e.g. resistance to infection). In addition, mouse ageing studies by their very nature tend to use specific pathogen-free environments to protect mice from infection. Therefore, under these experimental conditions, definitive measures of improved immune function are consequently difficult to assay. However, functional assays such as viral challenge may be useful in determining whether immune function is maintained in long-lived mice during ageing. Interestingly, intranasal inoculation with influenza (H1N1, PR8) actually increased mortality, increased weight loss and diminished innate immunity in male DR mice [98].

We previously reported that female Irs1−/− mice at 450 and 700 days of age [19] and female S6K1−/− mice at 600 days of age [29] had significantly fewer memory and more naive T cells relative to WT mice. This is suggestive of a more youthful immune profile in these animals. Interestingly, the age-related reduction in haematopoietic stem cell number linked to anaemia, impaired response to vaccination and tumourigenesis was reversed in old mice following rapamycin treatment [99].

Aged mice, like humans, are susceptible to several inflammatory pathologies, including dermatitis, gastritis, peritonitis and enteritis [50]. Both male and female Irs1−/− mice were completely resistant to the age-related ulcerative dermatitis observed in old C57BL/6 mice, whereas 25 per cent of WT mice were afflicted [19]. From 50 weeks of age onwards, long-lived Sp53/Sp16/SArf/TgTert mice were protected against age-related thinning of their epidermis and subcutaneous fat layer [50]. These mice also had higher skin keratinocyte telomerase activity, longer hair bulge and interfollicular epidermal telomeres, and higher clonogenic potential of epidermal stem cells at both young and old ages [50]. Sp53/Sp16/SArf/TgTert mice also had preserved intestinal tract epithelia during ageing and enhanced resistance to dextran sodium sulphate-induced intestinal ulcers [50]. PAPP-A-KO mice at 18 months of age are resistant to age-dependent thymic atrophy, have a more youthful T-cell profile and bone marrow enriched with thymus-seeding progenitor cells compared with controls [100]. MCAT mice also showed a trend towards less severe systemic inflammation [88]. Aged (27–29 months) Snell dwarfs are resistant to age-related changes in T-cell subsets, with preservation of their immune cell function and fewer P-glycoprotein (anergic)-expressing splenic cells [41]. However, as mentioned previously, the relationship between immune function and ageing appears incredibly complex. For example, long-lived Ames dwarf mice actually show various manifestations of immunodeficiency, in particular those relating to thymic function [101].

3. Conclusions

The application of mouse models to help inform what mechanisms underlie healthy ageing in mammals has provided exciting insights into this process but remains experimentally challenging. However, it is evident that despite these paradigm-shifting experiments, we still have no definitive mechanistic explanation of the ageing process, although enhanced resistance to oxidative stress ([102,103] but see also [104,105]), increased xenobiotic metabolism [106,107], altered mitochondrial function [108,109] and enhanced autophagy [110,111], for example, may be key, and not mutually exclusive, candidate mechanisms. Ames dwarf mice, for example, have enhanced paraquat resistance and lower liver and lung F(2) isoprostane levels in old age (14–20 months) compared with controls [112]. Fibroblasts from GH-deficient mice are also highly stress resistance [113,114], with Snell dwarfs fibroblasts showing enhanced antioxidant and base excision repair capacity following combined serum deprivation and paraquat exposure [115]. Therefore, we suggest that it is critical to determine whether parameters including stress resistance and base excision repair capacity are also altered in an age-dependent manner in other long-lived mouse models. Certainly, other mechanisms are also likely to be at work and full consideration is beyond the scope of this review, but are well covered elsewhere (e.g [116119]).

It is highly evident that using mammalian models to understand what underlies extended healthy lifespan is a rapidly expanding and competitive field of research. This is clearly indicated by the fact that seven long-lived genetic mouse models were described by 2003 [47] but over 20 models have been reported by 2009 [120]. The basic rationale for undertaking these long-term, demanding and expensive studies is to determine whether increased lifespan translates to increased healthspan in later life. Therefore, those studies that simultaneously measure lifespan, assay biomarkers predictive of lifespan [121] and examine age-related pathology are likely to be our best hope of identifying tractable interventions that can ultimately be applied to humans. In particular, we feel that future ageing studies should pay particular attention to late age health.


The authors are grateful to our co-workers and collaborators for their extensive contributions to our research. In addition, D.J.W. is grateful to the Wellcome Trust (Functional Genomics Award and Strategic Award), the Medical Research Council and Research into Ageing. D.J.W. and C.S. recognize support from the Biological and Biotechnology Research Council.


One contribution of 15 to a Discussion Meeting Issue ‘The new science of ageing’.


1. Christensen K., Doblhammer G., Rau R., Vaupel J. W. 2009. Ageing populations: the challenges ahead. Lancet 374, 1196–1208 (doi:10.1016/S0140-6736(09)61460-4)10.1016/S0140-6736(09)61460-4 [PMC free article] [PubMed] [Cross Ref]
2. Partridge L. 2010. The new biology of ageing. Phil. Trans. R. Soc. B 365, 147–154 (doi:10.1098/rstb.2009.0222)10.1098/rstb.2009.0222 [PMC free article] [PubMed] [Cross Ref]
3. Tomassini C. 2005. The demographic characteristics of the oldest old in the United Kingdom. Popul. Trends 120, 15–22 [PubMed]
4. Vaupel J. W. 2010. Biodemography of human ageing. Nature 464, 536–542 (doi:10.1038/nature08984)10.1038/nature08984 [PubMed] [Cross Ref]
5. Bishop N. A., Lu T., Yankner B. A. 2010. Neural mechanisms of ageing and cognitive decline. Nature 464, 529–535 (doi:10.1038/nature08983)10.1038/nature08983 [PMC free article] [PubMed] [Cross Ref]
6. Sarkar D., Fisher P. B. 2006. Molecular mechanisms of aging-associated inflammation. Cancer Lett. 236, 13–23 (doi:10.1016/j.canlet.2005.04.009)10.1016/j.canlet.2005.04.009 [PubMed] [Cross Ref]
7. Broughton S., Partridge L. 2009. Insulin/IGF-like signalling, the central nervous system and aging. Biochem. J. 418, 1–12 (doi:10.1042/BJ20082102)10.1042/BJ20082102 [PubMed] [Cross Ref]
8. Kenyon C. J. 2010. The genetics of ageing. Nature 464, 504–512 (doi:10.1038/nature08980)10.1038/nature08980 [PubMed] [Cross Ref]
9. Piper M. D., Selman C., McElwee J. J., Partridge L. 2008. Separating cause from effect: how does insulin/IGF signalling control lifespan in worms, flies and mice? J. Intern. Med. 263, 179–191 (doi:10.1111/j.1365-2796.2007.01906.x)10.1111/j.1365-2796.2007.01906.x [PubMed] [Cross Ref]
10. Masoro E. J. 2005. Overview of caloric restriction and ageing. Mech. Ageing Dev. 126, 913–922 (doi:10.1016/j.mad.2005.03.012)10.1016/j.mad.2005.03.012 [PubMed] [Cross Ref]
11. McCay C. M., Crowell L. A., Maynard L. A. 1935. The effect of retarded growth upon the length of life and upon the ultimate body size. J. Nutr. 10, 63–79 [PubMed]
12. Weindruch R., Walford R. L. 1988. The retardation of aging and disease by dietary restriction. Springfield, IL: Charles C. Thomas
13. Kenyon C. 2005. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (doi:10.1016/j.cell.2005.02.002)10.1016/j.cell.2005.02.002 [PubMed] [Cross Ref]
14. Partridge L., Gems D. 2007. Benchmarks for ageing studies. Nature 450, 165–167 (doi:10.1038/450165a)10.1038/450165a [PubMed] [Cross Ref]
15. Vijg J., Campisi J. 2008. Puzzles, promises and a cure for ageing. Nature 454, 1065–1071 (doi:10.1038/nature07216)10.1038/nature07216 [PMC free article] [PubMed] [Cross Ref]
16. Bluher M., Kahn B. B., Kahn C. R. 2003. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574 (doi:10.1126/science.1078223)10.1126/science.1078223 [PubMed] [Cross Ref]
17. Clancy D. J., Gems D., Harshman L. G., Oldham S., Stocker H., Hafen E., Leevers S. J., Partridge L. 2001. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292, 104–106 (doi:10.1126/science.1057991)10.1126/science.1057991 [PubMed] [Cross Ref]
18. Kappeler L., et al. 2008. Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol. 6, e254. (doi:10.1371/journal.pbio.0060254)10.1371/journal.pbio.0060254 [PMC free article] [PubMed] [Cross Ref]
19. Selman C., et al. 2008. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J. 22, 807–818 (doi:10.1096/fj.07-9261com)10.1096/fj.07-9261com [PubMed] [Cross Ref]
20. Pawlikowska L., et al. 2009. Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell 8, 460–472 (doi:10.1111/j.1474-9726.2009.00493.x)10.1111/j.1474-9726.2009.00493.x [PubMed] [Cross Ref]
21. Suh Y., Atzmon G., Cho M. O., Hwang D., Liu B., Leahy D. J., Barzilai N., Cohen P. 2008. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc. Natl Acad. Sci. USA 105, 3438–3442 (doi:10.1073/pnas.0705467105)10.1073/pnas.0705467105 [PubMed] [Cross Ref]
22. van Heemst D., Beekman M., Mooijaart S. P., Heijmans B. T., Brandt B. W., Zwaan B. J., Slagboom P. E., Westendorp R. G. 2005. Reduced insulin/IGF-1 signalling and human longevity. Aging Cell 4, 79–85 (doi:10.1111/j.1474-9728.2005.00148.x)10.1111/j.1474-9728.2005.00148.x [PubMed] [Cross Ref]
23. Masternak M. M., Panici J. A., Bonkowski M. S., Hughes L. F., Bartke A. 2009. Insulin sensitivity as a key mediator of growth hormone actions on longevity. J. Gerontol. A Biol. Sci. Med. Sci. 64, 516–521 (doi:10.1093/gerona/glp024)10.1093/gerona/glp024 [PMC free article] [PubMed] [Cross Ref]
24. Bjedov I., Toivonen J. M., Kerr F., Slack C., Jacobson J., Foley A., Partridge L. 2010. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (doi:10.1016/j.cmet.2009.11.010)10.1016/j.cmet.2009.11.010 [PMC free article] [PubMed] [Cross Ref]
25. Harrison D. E., et al. 2009. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (doi:10.1038/nature08221)10.1038/nature08221 [PMC free article] [PubMed] [Cross Ref]
26. Kaeberlein M. 2010. Resveratrol and rapamycin: are they anti-aging drugs? Bioessays 32, 96–99 (doi:10.1002/bies.200900171)10.1002/bies.200900171 [PubMed] [Cross Ref]
27. Kapahi P., Zid B. M., Harper T., Koslover D., Sapin V., Benzer S. 2004. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (doi:10.1016/j.cub.2004.03.059)10.1016/j.cub.2004.03.059 [PMC free article] [PubMed] [Cross Ref]
28. Pan K. Z., Palter J. E., Rogers A. N., Olsen A., Chen D., Lithgow G. J., Kapahi P. 2007. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 6, 111–119 (doi:10.1111/j.1474-9726.2006.00266.x)10.1111/j.1474-9726.2006.00266.x [PMC free article] [PubMed] [Cross Ref]
29. Selman C., et al. 2009. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (doi:10.1126/science.1177221)10.1126/science.1177221 [PubMed] [Cross Ref]
30. Evans W. J. 2010. Skeletal muscle loss: cachexia, sarcopenia, and inactivity. Am. J. Clin. Nutr. 91, 1123S–1127S (doi:10.3945/ajcn.2010.28608A)10.3945/ajcn.2010.28608A [PubMed] [Cross Ref]
31. Huffman D. M., Barzilai N. 2009. Role of visceral adipose tissue in aging. Biochim. Biophys. Acta 1790, 1117–1123 [PMC free article] [PubMed]
32. Karakelides H., Irving B. A., Short K. R., O'Brien P., Nair K. S. 2010. Age, obesity, and sex effects on insulin sensitivity and skeletal muscle mitochondrial function. Diabetes 59, 89–97 (doi:10.2337/db09-0591)10.2337/db09-0591 [PMC free article] [PubMed] [Cross Ref]
33. Tsugane S., Inoue M. 2010. Insulin resistance and cancer: epidemiological evidence. Cancer Sci. 101, 1073–1079 (doi:10.1111/j.1349-7006.2010.01521.x)10.1111/j.1349-7006.2010.01521.x [PubMed] [Cross Ref]
34. Healy L. A., Ryan A. M., Carroll P., Ennis D., Crowley V., Boyle T., Kennedy M. J., Connolly E., Reynolds J. V. 2010. Metabolic syndrome, central obesity and insulin resistance are associated with adverse pathological features in postmenopausal breast cancer. Clin. Oncol. UK 22, 281–288 (doi:10.1016/j.clon.2010.02.001)10.1016/j.clon.2010.02.001 [PubMed] [Cross Ref]
35. Naderali E. K., Ratcliffe S. H., Dale M. C. 2009. Obesity and Alzheimer's disease: a link between body weight and cognitive function in old age. Am. J. Alzheimers Dis. Other. Demen. 24, 445–449 (doi:10.1177/1533317509348208)10.1177/1533317509348208 [PubMed] [Cross Ref]
36. Bonkowski M. S., Rocha J. S., Masternak M. M., Al Regaiey K. A., Bartke A. 2006. Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc. Natl Acad. Sci. USA 103, 7901–7905 (doi:10.1073/pnas.0600161103)10.1073/pnas.0600161103 [PubMed] [Cross Ref]
37. Dominici F. P., Arostegui Diaz G., Bartke A., Kopchick J. J., Turyn D. 2000. Compensatory alterations of insulin signal transduction in liver of growth hormone receptor knockout mice. J. Endocrinol. 166, 579–590 (doi:10.1677/joe.0.1660579)10.1677/joe.0.1660579 [PubMed] [Cross Ref]
38. Dominici F. P., Hauck S., Argentino D. P., Bartke A., Turyn D. 2002. Increased insulin sensitivity and upregulation of insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2 in liver of Ames dwarf mice. J. Endocrinol. 173, 81–94 (doi:10.1677/joe.0.1730081)10.1677/joe.0.1730081 [PubMed] [Cross Ref]
39. Arum O., Bonkowski M. S., Rocha J. S., Bartke A. 2009. The growth hormone receptor gene-disrupted mouse fails to respond to an intermittent fasting diet. Aging Cell 8, 756–760 (doi:10.1111/j.1474-9726.2009.00520.x)10.1111/j.1474-9726.2009.00520.x [PMC free article] [PubMed] [Cross Ref]
40. Bartke A., Bonkowski M., Masternak M. 2008. THow diet interacts with longevity genes. Hormones (Athens) 7, 17–23 [PubMed]
41. Flurkey K., Papaconstantinou J., Miller R. A., Harrison D. E. 2001. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc. Natl Acad. Sci. USA 98, 6736–6741 (doi:10.1073/pnas.111158898)10.1073/pnas.111158898 [PubMed] [Cross Ref]
42. Hsieh C. C., DeFord J. H., Flurkey K., Harrison D. E., Papaconstantinou J. 2002. Implications for the insulin signaling pathway in Snell dwarf mouse longevity: a similarity with the C. elegans longevity paradigm. Mech. Ageing Dev. 123, 1229–1244 [PubMed]
43. Berryman D. E., List E. O., Palmer A. J., Chung M. Y., Wright-Piekarski J., Lubbers E., O'Connor P., Okada S., Kopchick J. J. 2010. Two-year body composition analyses of long-lived GHR null mice. J. Gerontol. A Biol. Sci. Med. Sci. 65, 31–40 (doi:10.1093/gerona/glp175)10.1093/gerona/glp175 [PMC free article] [PubMed] [Cross Ref]
44. Taguchi A., Wartschow L. M., White M. F. 2007. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317, 369–372 (doi:10.1126/science.1142179)10.1126/science.1142179 [PubMed] [Cross Ref]
45. Selman C., Lingard S., Gems D., Partridge L., Withers D. J. 2008. Comment on ‘Brain IRS2 signaling coordinates life span and nutrient homeostasis’. Science 320, 1012. (doi:10.1126/science.1152366)10.1126/science.1152366 [PubMed] [Cross Ref]
46. Holzenberger M., Dupont J., Ducos B., Leneuve P., Geloen A., Even P. C., Cervera P., Le Bouc Y. 2003. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (doi:10.1038/nature01298)10.1038/nature01298 [PubMed] [Cross Ref]
47. Liang H., Masoro E. J., Nelson J. F., Strong R., McMahan C. A., Richardson A. 2003. Genetic mouse models of extended lifespan. Exp. Gerontol. 38, 1353–1364 (doi:10.1016/j.exger.2003.10.019)10.1016/j.exger.2003.10.019 [PubMed] [Cross Ref]
48. Enns L. C., Morton J. F., Treuting P. R., Emond M. J., Wolf N. S., McKnight G. S., Rabinovitch P. S., Ladiges W. C. 2009. Disruption of protein kinase A in mice enhances healthy aging. PLoS ONE 4, e5963. (doi:10.1371/journal.pone.0005963)10.1371/journal.pone.0005963 [PMC free article] [PubMed] [Cross Ref]
49. Gonzalez-Suarez E., Samper E., Ramirez A., Flores J. M., Martin-Caballero J., Jorcano J. L., Blasco M. A. 2001. Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J. 20, 2619–2630 (doi:10.1093/emboj/20.11.2619)10.1093/emboj/20.11.2619 [PubMed] [Cross Ref]
50. Tomas-Loba A., et al. 2008. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135, 609–622 (doi:10.1016/j.cell.2008.09.034)10.1016/j.cell.2008.09.034 [PubMed] [Cross Ref]
51. Kurosu H., et al. 2005. Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833 (doi:10.1126/science.1112766)10.1126/science.1112766 [PMC free article] [PubMed] [Cross Ref]
52. Hebert L. E., Beckett L. A., Scherr P. A., Evans D. A. 2001. Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050. Alzheimer Dis. Assoc. Disord. 15, 169–173 (doi:10.1097/00002093-200110000-00002)10.1097/00002093-200110000-00002 [PubMed] [Cross Ref]
53. Kinney-Forshee B. A., Kinney N. E., Steger R. W., Bartke A. 2004. Could a deficiency in growth hormone signaling be beneficial to the aging brain? Physiol. Behav. 80, 589–594 (doi:10.1016/j.physbeh.2003.10.018)10.1016/j.physbeh.2003.10.018 [PubMed] [Cross Ref]
54. Kinney B. A., Coschigano K. T., Kopchick J. J., Steger R. W., Bartke A. 2001. Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice. Physiol. Behav. 72, 653–660 (doi:10.1016/S0031-9384(01)00423-1)10.1016/S0031-9384(01)00423-1 [PubMed] [Cross Ref]
55. Kinney B. A., Meliska C. J., Steger R. W., Bartke A. 2001. Evidence that Ames dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters. Horm. Behav. 39, 277–284 (doi:10.1006/hbeh.2001.1654)10.1006/hbeh.2001.1654 [PubMed] [Cross Ref]
56. Sun L. Y., Bartke A. 2007. Adult neurogenesis in the hippocampus of long-lived mice during aging. J. Gerontol. A Biol. Sci. Med. Sci. 62, 117–125 [PubMed]
57. Sun L. Y., Evans M. S., Hsieh J., Panici J., Bartke A. 2005. Increased neurogenesis in dentate gyrus of long-lived Ames dwarf mice. Endocrinology 146, 1138–1144 (doi:10.1210/en.2004-1115)10.1210/en.2004-1115 [PubMed] [Cross Ref]
58. Schrag M., Sharma S., Brown-Borg H., Ghribi O. 2008. Hippocampus of Ames dwarf mice is resistant to beta-amyloid-induced tau hyperphosphorylation and changes in apoptosis-regulatory protein levels. Hippocampus 18, 239–244 (doi:10.1002/hipo.20387)10.1002/hipo.20387 [PubMed] [Cross Ref]
59. Freude S., et al. 2009. Neuronal IGF-1 resistance reduces Abeta accumulation and protects against premature death in a model of Alzheimer's disease. FASEB J. 23, 3315–3324 (doi:10.1096/fj.09-132043)10.1096/fj.09-132043 [PubMed] [Cross Ref]
60. Killick R., et al. 2009. Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice. Biochem. Biophys. Res. Commun. 386, 257–262 (doi:10.1016/j.bbrc.2009.06.032)10.1016/j.bbrc.2009.06.032 [PMC free article] [PubMed] [Cross Ref]
61. Cohen E., et al. 2009. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139, 1157–1169 (doi:10.1016/j.cell.2009.11.014)10.1016/j.cell.2009.11.014 [PMC free article] [PubMed] [Cross Ref]
62. Caccamo A., Majumder S., Richardson A., Strong R., Oddo S. 2010. Molecular interplay between mTOR, amyloid-β, and Tau: effects on cognitive impairments. J. Biol. Chem. 285, 13 107–13 120 (doi:10.1074/jbc.M110.100420)10.1074/jbc.M110.100420 [PubMed] [Cross Ref]
63. Spilman P., Podlutskaya N., Hart M. J., Debnath J., Gorostiza O., Bredesen D., Richardson A., Strong R., Galvan V. 2010. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. PLoS ONE 5, e9979. (doi:10.1371/journal.pone.0009979)10.1371/journal.pone.0009979 [PMC free article] [PubMed] [Cross Ref]
64. Khosla S. 2010. Update in male osteoporosis. J. Clin. Endocrinol. Metab. 95, 3–10 (doi:10.1210/jc.2009-1740)10.1210/jc.2009-1740 [PubMed] [Cross Ref]
65. Crepaldi G., Maggi S. 2009. Epidemiologic link between osteoporosis and cardiovascular disease. J. Endocrinol. Invest. 32, 2–5 [PubMed]
66. Halloran B. P., Ferguson V. L., Simske S. J., Burghardt A., Venton L. L., Majumdar S. 2002. Changes in bone structure and mass with advancing age in the male C57BL/6J mouse. J. Bone Miner. Res. 17, 1044–1050 (doi:10.1359/jbmr.2002.17.6.1044)10.1359/jbmr.2002.17.6.1044 [PubMed] [Cross Ref]
67. Ogata N., et al. 2000. Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover. J. Clin. Invest. 105, 935–943 (doi:10.1172/JCI9017)10.1172/JCI9017 [PMC free article] [PubMed] [Cross Ref]
68. Yan L., et al. 2007. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 130, 247–258 (doi:10.1016/j.cell.2007.05.038)10.1016/j.cell.2007.05.038 [PubMed] [Cross Ref]
69. Silberberg R. 1972. Articular aging and osteoarthrosis in dwarf mice. Pathol. Microbiol. (Basel) 38, 417–430 [PubMed]
70. Pelletier A. L., Thomas J., Shaw F. R. 2009. Vision loss in older persons. Am. Fam. Physician 79, 963–970 [PubMed]
71. Turner P. L., Van Someren E. J., Mainster M. A. 2010. The role of environmental light in sleep and health: effects of ocular aging and cataract surgery. Sleep Med Rev. 14, 269–280 (doi:10.1016/j.smrv.2009.11.002)10.1016/j.smrv.2009.11.002 [PubMed] [Cross Ref]
72. Wolf N., Penn P., Pendergrass W., Van Remmen H., Bartke A., Rabinovitch P., Martin G. M. 2005. Age-related cataract progression in five mouse models for anti-oxidant protection or hormonal influence. Exp. Eye Res. 81, 276–285 [PubMed]
73. Vergara M., Smith-Wheelock M., Harper J. M., Sigler R., Miller R. A. 2004. Hormone-treated Snell dwarf mice regain fertility but remain long lived and disease resistant. J. Gerontol. A Biol. Sci. Med. Sci. 59, 1244–1250 [PMC free article] [PubMed]
74. Ran Q., Liang H., Ikeno Y., Qi W., Prolla T. A., Roberts L. J., II, Wolf N., Van Remmen H., Richardson A. 2007. Reduction in glutathione peroxidase 4 increases life span through increased sensitivity to apoptosis. J. Gerontol. A Biol. Sci. Med. Sci. 62, 932–942 [PubMed]
75. Murray C. J., Lopez A. D. 1997. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 349, 1269–1276 (doi:10.1016/S0140-6736(96)07493-4)10.1016/S0140-6736(96)07493-4 [PubMed] [Cross Ref]
76. Dai D. F., et al. 2009. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 119, 2789–2797 (doi:10.1161/CIRCULATIONAHA.108.822403)10.1161/CIRCULATIONAHA.108.822403 [PMC free article] [PubMed] [Cross Ref]
77. Schriner S. E., et al. 2005. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (doi:10.1126/science.1106653)10.1126/science.1106653 [PubMed] [Cross Ref]
78. Dai D. F., Chen T., Wanagat J., Laflamme M., Marcinek D. J., Emond M. J., Ngo C. P., Prolla T. A., Rabinovitch P. S. 2010. Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell 9, 536–544 (doi:10.1111/j.1474-9726.2010.00581.x)10.1111/j.1474-9726.2010.00581.x [PMC free article] [PubMed] [Cross Ref]
79. Yang X., Doser T. A., Fang C. X., Nunn J. M., Janardhanan R., Zhu M., Sreejayan N., Quinn M. T., Ren J. 2006. Metallothionein prolongs survival and antagonizes senescence-associated cardiomyocyte diastolic dysfunction: role of oxidative stress. FASEB J. 20, 1024–1026 (doi:10.1096/fj.05-5288fje)10.1096/fj.05-5288fje [PubMed] [Cross Ref]
80. Migliaccio E., Giorgio M., Mele S., Pelicci G., Reboldi P., Pandolfi P. P., Lanfrancone L., Pelicci P. G. 1999. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309–313 (doi:10.1038/46311)10.1038/46311 [PubMed] [Cross Ref]
81. Francia P., et al. 2004. Deletion of p66shc gene protects against age-related endothelial dysfunction. Circulation 110, 2889–2895 (doi:10.1161/01.CIR.0000147731.24444.4D)10.1161/01.CIR.0000147731.24444.4D [PubMed] [Cross Ref]
82. Graiani G., et al. 2005. Genetic deletion of the p66Shc adaptor protein protects from angiotensin II-induced myocardial damage. Hypertension 46, 433–440 (doi:10.1161/ [PubMed] [Cross Ref]
83. Harrington S. C., Simari R. D., Conover C. A. 2007. Genetic deletion of pregnancy-associated plasma protein-A is associated with resistance to atherosclerotic lesion development in apolipoprotein E-deficient mice challenged with a high-fat diet. Circ. Res. 100, 1696–1702 (doi:10.1161/CIRCRESAHA.106.146183)10.1161/CIRCRESAHA.106.146183 [PubMed] [Cross Ref]
84. Napoli C., et al. 2003. Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet. Proc. Natl Acad. Sci. USA 100, 2112–2116 (doi:10.1073/pnas.0336359100)10.1073/pnas.0336359100 [PubMed] [Cross Ref]
85. Ahmad A., Banerjee S., Wang Z., Kong D., Majumdar A. P., Sarkar F. H. 2009. Aging and inflammation: etiological culprits of cancer. Curr. Aging Sci. 2, 174–186 (doi:10.2174/1874609810902030174)10.2174/1874609810902030174 [PMC free article] [PubMed] [Cross Ref]
86. Vasto S., Carruba G., Lio D., Colonna-Romano G., Di Bona D., Candore G., Caruso C. 2009. Inflammation, ageing and cancer. Mech. Ageing Dev. 130, 40–45 (doi:10.1016/j.mad.2008.06.003)10.1016/j.mad.2008.06.003 [PubMed] [Cross Ref]
87. Anisimov V. N. 2001. Mutant and genetically modified mice as models for studying the relationship between aging and carcinogenesis. Mech. Ageing Dev. 122, 1221–1255 (doi:10.1016/S0047-6374(01)00262-7)10.1016/S0047-6374(01)00262-7 [PubMed] [Cross Ref]
88. Treuting P. M., Linford N. J., Knoblaugh S. E., Emond M. J., Morton J. F., Martin G. M., Rabinovitch P. S., Ladiges W. C. 2008. Reduction of age-associated pathology in old mice by overexpression of catalase in mitochondria. J. Gerontol. A Biol. Sci. Med. Sci. 63, 813–822 [PubMed]
89. Alderman J. M., et al. 2009. Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice. Exp. Gerontol. 44, 26–33 (doi:10.1016/j.exger.2008.05.014)10.1016/j.exger.2008.05.014 [PMC free article] [PubMed] [Cross Ref]
90. Ikeno Y., Lew C. M., Cortez L. A., Webb C. R., Lee S., Hubbard G. B. 2006. Do long-lived mutant and calorie-restricted mice share common anti-aging mechanisms?—a pathological point of view. Age (Dordr.) 28, 163–171 (doi:10.1007/s11357-006-9007-7)10.1007/s11357-006-9007-7 [PMC free article] [PubMed] [Cross Ref]
91. Ikeno Y., Bronson R. T., Hubbard G. B., Lee S., Bartke A. 2003. Delayed occurrence of fatal neoplastic diseases in Ames dwarf mice: correlation to extended longevity. J. Gerontol. A Biol. Sci. Med. Sci. 58, 291–296 (doi:10.1093/gerona/glp017)10.1093/gerona/glp017 [PubMed] [Cross Ref]
92. Ikeno Y., et al. 2009. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J. Gerontol. A Biol. Sci. Med. Sci. 64, 522–529 [PMC free article] [PubMed]
93. Conover C. A., Bale L. K. 2007. Loss of pregnancy-associated plasma protein A extends lifespan in mice. Aging Cell 6, 727–729 (doi:10.1111/j.1474-9726.2007.00328.x)10.1111/j.1474-9726.2007.00328.x [PubMed] [Cross Ref]
94. Harper J. M., Wilkinson J. E., Miller R. A. 2010. Macrophage migration inhibitory factor-knockout mice are long lived and respond to caloric restriction. FASEB J. 24, 2436–2442 (doi:10.1096/fj.09-152223)10.1096/fj.09-152223 [PubMed] [Cross Ref]
95. Miller R. A., Chrisp C. 2002. T cell subset patterns that predict resistance to spontaneous lymphoma, mammary adenocarcinoma, and fibrosarcoma in mice. J. Immunol. 169, 1619–1625 [PubMed]
96. Miller R. A. 2001. Biomarkers of aging: prediction of longevity by using age-sensitive T-cell subset determinations in a middle-aged, genetically heterogeneous mouse population. J. Gerontol. A Biol. Sci. Med. Sci. 56, B180–B186 [PubMed]
97. Miller R. A., Chrisp C., Galecki A. 1997. CD4 memory T cell levels predict life span in genetically heterogeneous mice. FASEB J. 11, 775–783 [PubMed]
98. Ritz B. W., Aktan I., Nogusa S., Gardner E. M. 2008. Energy restriction impairs natural killer cell function and increases the severity of influenza infection in young adult male C57BL/6 mice. J. Nutr. 138, 2269–2275 (doi:10.3945/jn.108.093633)10.3945/jn.108.093633 [PubMed] [Cross Ref]
99. Chen C., Liu Y., Zheng P. 2009. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75. (doi:10.1126/scisignal.2000559)10.1126/scisignal.2000559 [PubMed] [Cross Ref]
100. Vallejo A. N., Michel J. J., Bale L. K., Lemster B. H., Borghesi L., Conover C. A. 2009. Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A. Proc. Natl Acad. Sci. USA 106, 11 252–11 257 (doi:10.1073/pnas.0807025106)10.1073/pnas.0807025106 [PubMed] [Cross Ref]
101. Duquesnoy R. J. 1972. Immunodeficiency of the thymus-dependent system of the Ames dwarf mouse. J. Immunol. 108, 1578–1590 [PubMed]
102. Golden T. R., Hinerfeld D. A., Melov S. 2002. Oxidative stress and aging: beyond correlation. Aging Cell 1, 117–123 (doi:10.1046/j.1474-9728.2002.00015.x)10.1046/j.1474-9728.2002.00015.x [PubMed] [Cross Ref]
103. Hagen T. M. 2003. Oxidative stress, redox imbalance, and the aging process. Antioxid. Redox Signal. 5, 503–506 (doi:10.1089/152308603770310149)10.1089/152308603770310149 [PubMed] [Cross Ref]
104. Gems D., Doonan R. 2009. Antioxidant defense and aging in C. elegans: is the oxidative damage theory of aging wrong? Cell Cycle 8, 1681–1687 [PubMed]
105. Perez V. I., Bokov A., Van Remmen H., Mele J., Ran Q., Ikeno Y., Richardson A. 2009. Is the oxidative stress theory of aging dead? Biochim. Biophys. Acta 1790, 1005–1014 [PMC free article] [PubMed]
106. Gems D., McElwee J. J. 2005. Broad spectrum detoxification: the major longevity assurance process regulated by insulin/IGF-1 signaling? Mech. Ageing Dev. 126, 381–387 (doi:10.1016/j.mad.2004.09.001)10.1016/j.mad.2004.09.001 [PubMed] [Cross Ref]
107. McElwee J. J., et al. 2007. Evolutionarily conservation of regulated longevity assurance mechanisms. Genome Biol. 8, R132. (doi:10.1186/gb-2007-8-7-r132)10.1186/gb-2007-8-7-r132 [PMC free article] [PubMed] [Cross Ref]
108. Balaban R. S., Nemoto S., Finkel T. 2005. Mitochondria, oxidants, and aging. Cell 120, 483–495 (doi:10.1016/j.cell.2005.02.001)10.1016/j.cell.2005.02.001 [PubMed] [Cross Ref]
109. Van Remmen H., Jones D. P. 2009. Current thoughts on the role of mitochondria and free radicals in the biology of aging. J. Gerontol. A Biol. Sci. Med. Sci 64, 171–174 [PMC free article] [PubMed]
110. Cuervo A. M., Bergamini E., Brunk U. T., Droge W., Ffrench M., Terman A. 2005. Autophagy and aging: the importance of maintaining ‘clean’ cells. Autophagy 1, 131–140 (doi:10.4161/auto.1.3.2017)10.4161/auto.1.3.2017 [PubMed] [Cross Ref]
111. Terman A., Gustafsson B., Brunk U. T. 2007. Autophagy, organelles and ageing. J. Pathol. 211, 134–143 (doi:10.1002/path.2094)10.1002/path.2094 [PubMed] [Cross Ref]
112. Bokov A. F., Lindsey M. L., Khodr C., Sabia M. R., Richardson A. 2009. Long-lived Ames dwarf mice are resistant to chemical stressors. J. Gerontol. A Biol. Sci. Med. Sci. 64, 819–827 (doi:10.1093/gerona/glp052)10.1093/gerona/glp052 [PMC free article] [PubMed] [Cross Ref]
113. Murakami S., Salmon A., Miller R. A. 2003. Multiplex stress resistance in cells from long-lived dwarf mice. FASEB J. 17, 1565–1566 [PubMed]
114. Salmon A. B., Murakami S., Bartke A., Kopchick J., Yasumura K., Miller R. A. 2005. Fibroblast cell lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress. Am. J. Physiol. Endocrinol. Metab. 289, E23–E29 (doi:10.1152/ajpendo.00575.2004)10.1152/ajpendo.00575.2004 [PubMed] [Cross Ref]
115. Page M. M., Salmon A. B., Leiser S. F., Robb E. L., Brown M. F., Miller R. A., Stuart J. A. 2009. Mechanisms of stress resistance in Snell dwarf mouse fibroblasts: enhanced antioxidant and DNA base excision repair capacity, but no differences in mitochondrial metabolism. Free Radic. Biol. Med. 46, 1109–1118 (doi:10.1016/j.freeradbiomed.2009.01.014)10.1016/j.freeradbiomed.2009.01.014 [PMC free article] [PubMed] [Cross Ref]
116. Campisi J. 2005. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (doi:10.1016/j.cell.2005.02.003)10.1016/j.cell.2005.02.003 [PubMed] [Cross Ref]
117. Kirkwood T. B. 2005. Understanding the odd science of aging. Cell 120, 437–447 (doi:10.1016/j.cell.2005.01.027)10.1016/j.cell.2005.01.027 [PubMed] [Cross Ref]
118. Lombard D. B., Chua K. F., Mostoslavsky R., Franco S., Gostissa M., Alt F. W. 2005. DNA repair, genome stability, and aging. Cell 120, 497–512 (doi:10.1016/j.cell.2005.01.028)10.1016/j.cell.2005.01.028 [PubMed] [Cross Ref]
119. Partridge L., Gems D., Withers D. J. 2005. Sex and death: what is the connection? Cell 120, 461–472 (doi:10.1016/j.cell.2005.01.026)10.1016/j.cell.2005.01.026 [PubMed] [Cross Ref]
120. Ladiges W., Van Remmen H., Strong R., Ikeno Y., Treuting P., Rabinovitch P., Richardson A. 2009. Lifespan extension in genetically modified mice. Aging Cell 8, 346–352 (doi:10.1111/j.1474-9726.2009.00491.x)10.1111/j.1474-9726.2009.00491.x [PubMed] [Cross Ref]
121. Ingram D. K., Nakamura E., Smucny D., Roth G. S., Lane M. A. 2001. Strategy for identifying biomarkers of aging in long-lived species. Exp. Gerontol. 36, 1025–1034 (doi:10.1016/S0531-5565(01)00110-3)10.1016/S0531-5565(01)00110-3 [PubMed] [Cross Ref]
122. Brown-Borg H. M., Borg K. E., Meliska C. J., Bartke A. 1996. Dwarf mice and the ageing process. Nature 384, 33. (doi:10.1038/384033a0)10.1038/384033a0 [PubMed] [Cross Ref]
123. Coschigano K. T., Clemmons D., Bellush L. L., Kopchick J. J. 2000. Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141, 2608–2613 (doi:10.1210/en.141.7.2608)10.1210/en.141.7.2608 [PubMed] [Cross Ref]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society