Prace poglądowe/Reviews |
|
Links between growth hormone and aging
Hormon wzrostu a proces starzenia się
Andrzej Bartke1, 2, Reyhan Westbrook1, Liou Sun1, Mariusz Ratajczak3
1Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL, United States
2Department of Physiology, Southern Illinois University School of Medicine, Springfield, IL, United States
3Department of Medicine, University of Louisville, Louisville, KY, United States
|
Andrzej Bartke M.D., Ph.D. Geriatric Research, Department of Medicine, Southern Illinois University School of Medicine, P.O. Box 19628, Springfield, IL 62794–9628, USA, tel.: 217 545 7962, fax: 217 545 8006, e-mail: abartke@siumed.edu |
Abstract
Studies in mutant, gene knock-out and transgenic mice have demonstrated that growth hormone (GH) signalling has a major impact on ageing and longevity. Growth hormone-resistant and GH-deficient animals live much longer than their normal siblings, while transgenic mice overexpressing GH are short lived. Actions of GH in juvenile animals appear to be particularly important for life extension and responsible for various phenotypic characteristics of long-lived hypopituitary mutants.
Available evidence indicates that reduced GH signalling is linked to extended longevity by multiple interacting mechanisms including increased stress resistance, reduced growth, altered profiles of cytokines produced by the adipose tissue, and various metabolic adjustments such as enhanced insulin sensitivity, increased oxygen consumption (VO2/g) and reduced respiratory quotient. The effects of removing visceral fat indicate that increased levels of adiponectin and reduced levels of pro-inflammatory cytokines in GH-resistant mice are responsible for their increased insulin sensitivity. Increased VO2 apparently represents increased energy expenditure for thermogenesis, because VO2 of mutant and normal mice does not differ at thermoneutral temperature. Recent studies identified GH- and IGF-1-dependent maintenance of bone marrow populations of very small embryonic-like stem cells (VSELs) as another likely mechanism of delayed ageing and increased longevity of GH-deficient and GH-resistant animals.
Many of the physiological characteristics of long-lived, GH-related mouse mutants are shared by exceptionally long-lived people and by individuals genetically predisposed to longevity. (Endokrynol Pol 2013; 64 (1): 46–52)
Key words: growth hormone (GH), calorie restriction (CR), insulin-like growth factor (IGF-1), Ames dwarf mice, growth hormone receptor knockout (GHRKO) mice
Streszczenie
W badaniach na zmutowanych i transgenicznych myszach wykazano, że przekazywanie sygnałów przez hormon wzrostu (GH) wywiera istotny wpływ na procesy starzenia się organizmu i długowieczność. Zwierzęta, u których stwierdza się oporność na hormon wzrostu lub jego niedobór, żyją dłużej niż ich normalne rodzeństwo, podczas gdy myszy transgeniczne wykazujące nadekspresję GH żyją krótko. Działania, jakie wywiera GH u młodocianych zwierząt wydają się odgrywać szczególnie ważną rolę w wydłużaniu życia i są odpowiedzialne za różnorodne cechy fenotypowe długowiecznych mutantów z niedoczynnością przysadki.
Z dostępnych dowodów naukowych wynika, że osłabione przekazywanie sygnałów przez GH wiąże się ze zwiększeniem długowieczności, u podstawy czego leży wiele współzależnych mechanizmów obejmujących zwiększoną odporność na stres, osłabione wzrastanie, zmieniony profil cytokin wytwarzanych przez tkankę tłuszczową, a także różne adaptacje metaboliczne, np. zwiększona insulinowrażliwość, zwiększone zużycie tlenu (VO2/g) i zmniejszony współczynnik oddechowy. Konsekwencje usunięcia trzewnej tkanki tłuszczowej wskazują, i że zwiększoną insulinowrażliwość u myszy opornych na GH odpowiedzialne jest zwiększone stężenie adyponektyny i zmniejszone stężenie cytokin prozapalnych. Zwiększone VO2 wydaje się wynikać ze zwiększenia wydatkowania energii na termogenezę, bowiem w temperaturze termoneutralnej VO2 u myszy zmutowanych i myszy niezmutowanych nie różni się. W najnowszych badaniach — jako kolejny prawdopodobny mechanizm opóźnionego starzenia się organizmu i zwiększonej długowieczności u zwierząt z niedoborem GH i opornością na GH — zidentyfikowano zależne od GH i IGF1 podtrzymywanie szpikowych populacji bardzo małych komórek macierzystych podobnych do zarodkowych (VSEL, very small embryonic-like stem cells).
Wiele z cech fizjologicznych długowiecznych myszy z mutacjami związanymi z GH występuje też u bardzo długo żyjących ludzi i osób genetycznie predysponowanych do długowieczności. (Endokrynol Pol 2013; 64 (1): 46–52)
Słowa kluczowe: hormon wzrostu (GH), ograniczenie kaloryczne, insulinopodobny czynnik wzrostu 1 (IGF1), myszy karłowate szczepu Ames, myszy z wyłączonym genem kodującym receptor hormonu wzrostu (GHRKO)
Introduction
In laboratory populations of house mice (Mus musculus), the strength of growth hormone (GH) signals is a major determinant of ageing and longevity. In transgenic mice expressing various GH genes under the control of metallothionein or phosphoenolpyruvate carboxykinase promoters, massive overproduction of GH leads to drastically reduced lifespan and many symptoms of accelerated ageing [1]. In contrast, GH deficiency in hypopituitary mutants and GH resistance in mice with targeted deletion of GH receptors are associated with approximately 30%–60% lifespan extension, depending on the mutation involved, genetic background, sex and diet composition [2–5]. Importantly, GH-deficient and GH-resistant mice exhibit many symptoms of delayed ageing and have an extended ‘health span’ i.e. a period of life free from major disease or functional impairments [3, 5, 6].
The incidence of fatal neoplastic disease is reduced, and its onset delayed, in these long-lived GH-related mutants [7–9]. Studies of the phenotypes of these mutant animals have revealed partial overlap with the characteristics of genetically normal mice subjected to long-term calorie restriction (CR; a life-extending intervention) and identified a number of very likely (although at this time not conclusively proven) candidate mechanisms of their delayed ageing and extended longevity. These mechanisms include enhanced activity of antioxidant enzymes and reduced oxidative damage [10, 11]; increased cellular resistance to a variety of toxic substances and stressful conditions [12, 13]; reduced activity of a nutrient-sensing mammalian target of rapamycin (mTOR) pathway that regulates translation and growth [14, 15]; and improved sensitivity to insulin coexisting with reduced insulin levels [15–17]. Importantly, negative association of GH action with longevity discovered in mutant, gene knock-out and transgenic mice also applies to genetically normal (‘wild-type’) animals. Comparisons of mice from different strains, as well as individual animals from a genetically heterogeneous normal population, has revealed that smaller animals live longer [18, 19], and circulating levels of insulin-like growth factor 1 (IGF-1, the key mediator of GH stimulatory action on somatic growth) are negatively correlated with longevity [19, 20].
The ground-breaking discovery of significant homology of longevity genes of a tiny, free-living worm, Caenorhabditis elegans, with mammalian genes involved in insulin and IGF-1 signalling [21, 22] led to identification of a conserved pathway of endocrine signalling that controls ageing and longevity in organisms ranging from yeast to mammals [23, 24]. This pathway comprises multiple insulin-like and IGF-like hormones in worms and insects, insulin and IGF in vertebrates, the corresponding receptors (one in worms and insects but several in invertebrates) as well as their signalling intermediates including insulin receptor substrates, phospatidylinositol kinase, protein kinase B (Akt) and an important FOXO family of transcription factors that indirectly control cellular defences from oxidative stress along with other functions. In mammals, GH is intimately involved in the functioning of this pathway by serving as the key determinant of hepatic IGF-1 expression and circulating IGF-1 levels. It also acts as a counter-regulatory hormone in carbohydrate homeostasis by promoting insulin resistance and exerting various anti-insulinaemic effects.
While pathological excess of GH secretion reduces life expectancy in people as it does in mice [1, 25], the impact of hypopituitarism, GH deficiency and GH resistance on human longevity is poorly understood, controversial and probably relatively minor [26–28]. However, individuals with genetic GH deficiency or GH resistance are remarkably, and in some cases apparently completely, protected from major age-related diseases including atherosclerosis, diabetes and, most strikingly, cancer [26, 27, 29–31].
In this article, we will briefly review and discuss some recent findings in GH-deficient and GH-resistant mice that identify novel candidate mechanisms of their extended longevity and raise new questions about relationships between somatotropic (GH;IGF) signalling and ageing.
Energy metabolism and role of ambient (environmental) temperature
Indirect calorimetry studies have revealed that in both hypopituitary Ames dwarf (Prop1df) and insulin-resistant GH receptor-deleted (GHRKO) mice, oxygen consumption (VO2) per gram of body weight is increased during both active (dark) and resting (light) portions of the 24 h period [32]. These differences were evident regardless of the presence or absence of food during recording and were accompanied by a reduction in respiratory quotient (RQ) [32]. Respiratory quotient represents ratio of carbon dioxide produced to oxygen consumed and provides an estimate of the relative amounts of carbohydrate vs. lipids (primarily fatty acids) utilised as energy substrates.
The finding that long-lived dwarf mice have increased metabolic rate (as assessed by VO2) was counterintuitive and contrary to our expectations because these animals have reduced levels of anabolic and thermogenic hormones, GH, IGF-1 and insulin. Ames dwarf mice are also severely hypothyroid. However, the observed differences were relatively large and reproducible, and apparently did not represent an artifact of the fact that this data was expressed per unit of body mass rather than per unit of calculated lean or ‘metabolic’ body mass. Estimates of lean body mass are based on the assumption that smaller animals are proportionally leaner, while the amount of adipose tissue in these mutants is either increased or nearly normal (depending on the mutation, sex and age) [33–35]. When we re-calculated VO2 data in GHRKO and normal mice in terms of the actual percent of lean body mass as determined by dual energy X-ray absorptiometry (DEXA), the increase of VO2 in the mutants not only persisted but became exaggerated [Westbrook and Bartke, unpublished].
In small animals maintained in a standard animal room temperature (approx. 23oC), a considerable proportion of the energy budget is devoted to thermogenesis. Consequently, we suspected that the increase in VO2 in dwarf mice may reflect increased energy demand for compensation for the increased heat loss by radiation in these diminutive animals. This compensation would allow them to maintain stable body temperature. To test the validity of this hypothesis, we repeated indirect calorimetry studies in GHRKO and normal mice at a thermoneutral temperature, which in mice is approximately 30oC. In the thermoneutral environment, the metabolic rate decreased as expected, but this decrease was incomparably greater in GHRKO than in normal mice. As a result, the difference in VO2 between the normal and mutant animals disappeared [Westbrook and Bartke, unpublished]. It is tempting to speculate that, at a standard animal room temperature, increased thermogenesis in dwarf mice leads to greater utilisation of lipids as an energy source (‘fat burning’) and more efficient function of mitochondria with reduced production of reactive oxygen species, and that these metabolic adaptations contribute to the extended longevity of these animals. In support of these speculations, similar metabolic adaptations develop in response to calorie restriction, and some of the beneficial effects of calorie restriction were reported to be attenuated if the mice were housed at a thermoneutral temperature [36].
Inflammation; secretory activity of adipose tissue
There is considerable, although largely only correlative, evidence that inflammatory processes and circulating inflammation markers are involved in the control of human ageing, age-related disease and longevity [37, 38]. Growth hormone has been reported to exert both anti- and pro-inflammatory effects [39-41], while inflammation can influence GH release and actions [42, 43]. Available information indicates that the expression as well as tissue and blood levels of pro-inflammatory cytokines, interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α) are reduced in long-lived GH-deficient and GH-resistant mice [44, 45]. Moreover, circulating levels of an anti-inflammatory adipokine, adiponectin, are consistently elevated in these animals [15, 45]. This latter observation was unexpected because the absence of GH signals in these mutants leads to increased adiposity, and because, in both laboratory animals and humans, plasma levels of adiponectin have been repeatedly shown to be inversely rather than directly related to adiposity. Thus, circulating adiponectin levels are normally reduced in obese individuals, while leanness and calorie restriction are associated with increased plasma adiponectin. Apparently, in Ames dwarf and in GHRKO mice, absence of GH action overrides the influence of increased adiposity on adiponectin secretion. In support of this interpretation, over-expressing GH adiposity in transgenic mice is reduced, and yet adiponectin levels are reduced rather than elevated [46].
Because adiponectin promotes insulin sensitivity, increased adiponectin levels in GHRKO and Ames dwarf mice are consistent with improved insulin signalling in these animals, and indeed provide a very plausible explanation as to why these generally obese animals are insulin sensitive rather than insulin resistant. It is also likely that the anti-inflammatory and anti-atherogenic activity of adiponectin contribute to the extension of health span and lifespan in these mutants.
Recent studies involving surgical removal of visceral adipose tissue have provided strong support for the suspected role of increased adiponectin levels in the enhancement of insulin sensitivity in GHRKO mice. Visceral fat is an important source of cytokines, and in obese individuals it is believed to be involved in producing a state of chronic, low-grade inflammation leading to insulin resistance and increased risk of age-related disease. Consistent with this role of visceral fat in glucose homeostasis and ageing, surgical removal of most of the abdominal fat from male rats resulted in improved insulin sensitivity and a significant extension of lifespan [46]. To address the paradox of the coexistence of obesity and enhanced insulin sensitivity in GHRKO mice, we compared the effects of removing visceral (epididymal and perinephric) fat in GHRKO and normal mice. In normal animals, visceral fat removal improved insulin sensitivity (measured by insulin tolerance tests, ITT) and clearance of injected glucose (measured in glucose tolerance tests, GTT), as anticipated. In contrast, in GHRKO mice, the same surgical procedure led to a reduction of plasma adiponectin levels and deterioration of glucose homeostasis as measured by ITT and GTT [47].
Studies of epididymal fat pads confirmed increased expression of adiponectin and reduced expression of interleukin 6 (IL-6) in GHRKO compared to normal mice [47]. It can be concluded that, in the absence of GH signals, the secretory profile of adipose tissue (or perhaps, specifically, intraabdominal adipose tissue) is shifted from pro-inflammatory to anti-inflammatory adipokines. This shift importantly contributes to paradoxically improved insulin signalling in obese GHRKO males. Together with the documented anti-atherogenic actions of adiponectin, these changes probably contribute to the extension of longevity in GHRKO mice. Studies of gene expression in peripheral blood leukocytes in Ames dwarf mice have indicated that activation of anti-inflammatory pathways in long-lived GH-related mutants extends beyond the adipose tissue [48].
Intriguingly, some of the interactions between inflammatory processes and metabolism demonstrated in mutant mice appear to also apply to humans. In humans, as in mice, the absence of GH signals leads to obesity, which is strongly associated with insulin resistance and increased risk of chronic disease. However, hereditary GH resistance in an extensively studied population of individuals with Laron dwarfism in Ecuador was associated with striking, nearly complete, protection from cancer and diabetes [27]. Moreover, a cohort of GH-deficient dwarfs studied in Brazil was shown to be unexpectedly protected from atherosclerosis in spite of obesity and unfavourable serum lipid profiles [26].
Maintenance of bone marrow populations of pluripotent stem cells
Although the role of stem cells in the control of longevity and protection from age-related disease remains to be fully elucidated, there is considerable evidence for their involvement in the maintenance and repair of adult tissues [49–52]. A population of pluripotent very small embryonic-like stem cells (VSELs) in the bone marrow has been identified on the basis of a unique combination of markers and ability to differentiate into a wide variety of cell types in vitro [53–57]. It has been postulated that these developmentally primitive cells are dormant precursors of more restricted tissue-committed stem cells, and thus play a role in steady state conditions in tissue organ rejuvenation and regeneration after injury [57]. In mice, the number of VSELs in the bone marrow declines with age [58], and their maintenance has been linked to the control of methylation state of a number of imprinted genes related to IGF signalling [59]. It was therefore interesting to assess the abundance of VSELs in GH-related mutants in which circulating levels of IGF-1 are dramatically suppressed. Results of these studies revealed that the numbers of VSELs are greater in Ames dwarf and GHRKO mice than in normal animals from the same strains [60, 61 and unpublished observations]. These differences were large, with little or no overlap between the values measured in mutant and normal animals, and were present in both young adult and middle-aged mice [60, 61 and unpublished observations]. In interesting contrast, the number of VSELs was reduced in GH transgenic mice in which circulating IGF-1 levels are chronically elevated [62]. Hormonal replacement therapy with GH in Ames dwarf mice and with IGF-1 in GHRKO animals, as well as treatment of normal mice with large doses of GH, reduced the number of VSELs in their bone marrow [61]. These results clearly establish that in animals with GH deficiency or GH resistance and the consequent suppression of plasma IGF-1 levels, the abundance of VSELs in the bone marrow is increased, probably reflecting reduced differentiation and/or other mechanisms of age-dependent depletion.
In the same studies, the effects of altered GH levels or actions on the number of haematopoietic stem cells were generally parallel to the above-described impact on the number of VSELs [60–62]. It is interesting to speculate that the observed relationships between the activity of the somatotropic axis and the populations of VSELs may apply more broadly, and include various categories of stem and progenitor cells. This in turn could prove important for the repair and maintenance of different tissues and organs and thus may represent yet another mechanism that links reduced GH/IGF-1 signalling with the extension of health span and lifespan.
Impact of prepubertal GH signalling on longevity
Failure of somatotroph differentiation and the resulting GH deficiency in Ames (Prop1-df) and Snell (Pit1-dw) mice led to dramatic reductions in the rate of postnatal growth and adult body size. These mutants are also thyroid-stimulating hormone (TSH) and prolactin (PRL) deficient [51]. The effects of treating dwarf mice with thyroxine (T4) or PRL indicate that hypothyroidism resulting from TSH deficiency contributes to the reduced growth and adult size of these animals. The role of PRL deficiency in reduced growth of these mutants is less clear and almost certainly minor. The unexpected remarkable increase of longevity of both Ames and Snell dwarf mice, as well as in other GH-related mutants, raised a question of the possible significance of the rate of postnatal growth in the determination of lifespan. The fact that the negative correlation of longevity with adult body size detected in mutant, gene knock-out and transgenic mice also applies to genetically normal mice [18, 19], domestic dogs [55] and other species [56, 57] provided additional rationale for probing the role of post-natal growth in the determination of longevity.
Studies conducted in the Miller laboratory in Snell dwarf mice [58], as well as our initial studies in Ames dwarfs, demonstrated that treatment of juvenile dwarf mice with GH, T4 or a combination of GH and T4 produced the expected increase in body weight and length. Longevity, however, was not affected. In these studies, Snell dwarfs were given hormonal treatments between four and 15 weeks of age, while Ames dwarf mice were injected with GH (once daily), T4 (three times per week) or both starting at two weeks of age and continuing for six weeks. In a follow-up study, we have increased the dose of GH as well as the frequency of injections (twice a day on weekdays and once a day on weekends) and observed a major reduction in the longevity of GH-treated Ames dwarf mice [59]. During the period of GH treatment, these animals grew at a rate roughly comparable to the growth of normal mice; but when the treatment was stopped, their growth rate levelled off and their adult body size was intermediate between the size of normal mice and control (vehicle-injected) dwarfs. Thus, it would appear that GH signalling during the normally rapid early (prepubertal) growth has an important role in the determination of ageing and lifespan. Preliminary data derived from recent and ongoing studies in our laboratory suggests that this ’critical period’ of the action of GH on lifespan begins fairly early (during the period of suckling), and there are some intriguing indications that it may be advanced and/or shortened by treatment with T4 [Spong and Bartke, unpublished].
The importance of early ‘developmental’ effects of GH in the determination of lifespan was not expected because GH is believed to have a very limited role, if any, in the control of pre-weaning growth in rodents [60]. However, the involvement of early postnatal events in the determination of longevity received strong support from the recent demonstration in the Miller laboratory that reducing pre-weaning growth in genetically normal mice by increasing the number of pups suckled by one female significantly extends their average and maximal lifespan [61].
Working with dwarf rats, which have reduced somatotropic signalling but normal lifespan, Sonntag et al. reported that twice-daily injections of GH between the ages of four and 14 weeks led to a significant increase in longevity [62].
Although more work is obviously needed to fully reconcile findings in different species and in long-lived mutants vs. normal animals, it appears to be justified to conclude that ageing and lifespan are significantly related to early postnatal growth and to the actions of GH during this period. This might appear counterintuitive, but is not surprising when viewed in the light of the well-documented early (‘organisational’) effects of steroid hormones on reproductive behaviour, fertility and responses to stress. Moreover, there is rapidly accumulating evidence for the important impact of early, nutrition-related ‘developmental programming’ on adult metabolism and susceptibility to chronic disease [63, 64].
We are currently searching for mechanisms that may link GH actions in juvenile animals with ageing and longevity. As the initial step, we are interested in identifying longevity-related traits that are influenced by early GH therapy and remain altered after GH treatment is stopped. The most recent data suggests that GH-induced insulin resistance is not a likely mechanism of shortened lifespan in GH-injected dwarfs. However, increased oxygen consumption per unit body mass (VO2/g) and reduced respiratory quotient (RQ), which we have previously identified as metabolic characteristics of Ames dwarf and GHRKO mice [32], were completely (VO2) or partially (RQ) normalised (‘rescued’) in GH-injected dwarfs five months after completion of GH therapy [Westbrook and Bartke, unpublished]. Adult hepatic expression of genes coding for several detoxification enzymes was also normalised by treatment of Ames dwarf mice with GH between two and eight weeks of age [Sun and Bartke, unpublished]. In as much as improved mitochondrial function, increased utilisation of fatty acids for energy metabolism (as indicated by reduced RQ), and improved breakdown (detoxification) of xenobiotics are probable contributors to the extended longevity of Ames dwarf versus normal mice, the elimination or suppression of these characteristics in GH-injected dwarfs may represent candidate mechanisms of reduced life expectancy.
Conclusion
Studies in mutant, gene knock-out and transgenic animals with extreme, well-defined, hereditary alterations in somatotropic signalling have revealed a prominent role of GH in the control of mammalian ageing and identified multiple interactive mechanisms that appear to be responsible for these relationships. It is hoped that further studies in these animals will help clarify the mechanisms by which GH influences ageing and elucidate the role of variations in the somatotropic axis activity within the normal (physiological) range in the control of ageing in genetically normal (‘wild-type’) animals and in humans.
Acknowledgements
Our current studies of this topic and preparation of this chapter were supported by National Institute on Aging grants RO1AGO19899, PO1 AG31736 and R21 AG038850 and Southern Illinois University School of Medicine Geriatrics Research Initiative.
References
- 1. Bartke A. Can growth hormone accelerate aging? Evidence from GH-transgenic mice. Neuroendocrinology 2003; 78: 210–216.
- 2. Brown-Borg HM, Borg KE, Meliska CJ et al. Dwarf mice and the aging process. Nature 1996; 384: 33.
- 3. Flurkey K, Papaconstantinou J, Miller RA et al. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci USA 2001; 98: 6736–6741.
- 4. Coschigano KT, Holland AN, Riders ME et al. Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 2003; 144: 3799–3810.
- 5. Bartke A. Single-gene mutations and healthy ageing in mammals. Philos Trans R Soc Lond B Biol Sci 2011; 366: 28–34.
- 6. Kinney BA, Meliska CJ, Steger RW, Bartke A. Evidence that Ames dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters. Horm Behav 2001; 39: 277–284.
- 7. Ikeno Y, Bronson RT, Hubbard GB, Bartke A. Delayed occurrence of fatal neoplastic diseases in ames dwarf mice: correlation to extended longevity. J Gerontol A Biol Sci Med Sci 2003; 58: 291–296.
- 8. Ikeno Y, Hubbard GB, Lee S et al. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J Gerontol A Biol Sci Med Sci 2009; 64: 522–529.
- 9. Vergara M, Smith-Wheelock M, Harper JM et al. Hormone-treated Snell dwarf mice regain fertility but remain long lived and disease resistant. J Gerontol A Biol Sci Med Sci 2004; 59: 1244–1250.
- 10. Brown-Borg H, Johnson WT, Rakoczy S et al. Mitochondrial oxidant generation and oxidative damage in Ames dwarf and GH transgenic mice. J Amer Aging Assoc 2001; 24: 85–96.
- 11. Brown-Borg H. Longevity in mice: is stress resistance a common factor? Age (Dordr) 2006: 28: 145–162.
- 12. Salmon AB, Murakami S, Bartke A et al. Fibroblast cell lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress. Am J Physiol Endocrinol Metab 2005; 289: E23–E29.
- 13. Page MM, Salmon AB, Leiser SF et al. 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 2009; 46: 1109–1118.
- 14. Sharp ZD, Bartke A. Evidence for down-regulation of phosphoinositide 3 kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR)-dependent translation regulatory signaling pathways in Ames dwarf mice. J Gerontol A Biol Sci Med Sci 2005; 60: 293–300.
- 15. 15. Al-Regaiey KA, Masternak MM, Bonkowski M et al. Long-lived growth hormone receptor knockout mice: interaction of reduced insulin-like growth factor 1/insulin signaling and caloric restriction. Endocrinology 2005; 146: 851–860.
- 16. Bonkowski MS, Rocha JS, Masternak MM et al. Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc Natl Acad Sci USA 2006; 103: 7901–7905.
- 17. Masternak MM, Panici JA, Bonkowski MS et al. Insulin sensitivity as a key mediator of growth hormone actions on longevity. J Gerontol A Biol Sci Med Sci 2009; 64: 516–521.
- 18. Roberts RC. The lifetime growth and reproduction of selected strains of mice. Heredity 1961; 16: 369–381.
- 19. Miller RA, Harper JM, Galecki A et al. Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice. Aging Cell 2002; 1: 22–29.
- 20. Yuan R, Tsaih SW, Petkova SB et al. Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 2009; 8: 277–287.
- 21. Tissenbaum HA, Ruvkun G. An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans. Genetics 1998; 148: 703–717.
- 22. Kimura KD, Tissenbaum HA, Liu Y et al. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 1997; 277: 942–946.
- 23. Tatar M, Bartke A, Antebi A. The endocrine regulation of aging by insulin-like signals. Science 2003; 299: 1346–1351.
- 24. Longo VD, Finch CE. Evolutionary medicine: from dwarf model systems to healthy centenarians? Science 2003; 299: 1342–1346.
- 25. Jadresic A, Banks LM, Child DF et al. The acromegaly syndrome. Relation between clinical features, growth hormone values and radiological characteristics of the pituitary tumours. Q J Med 1982; 51: 189–204.
- 26. Oliveira JL, Aguiar-Oliveira MH, D’Oliveira A, Jr. et al. Congenital growth hormone (GH) deficiency and atherosclerosis: effects of GH replacement in GH-naive adults. J Clin Endocrinol Metab 2007; 92: 4664–4670.
- 27. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 2011; 3: 70ra13.
- 28. Burgers AM BN, Schoones JW, Pereira AM et al. Meta-analysis and dose-response metaregression: Circulating insulin-like growth factor I (IGF-1) and mortality. J Clin Endocrinol Metab 2011; 96: 2912–2920.
- 29. Shechter M, Ginsberg S, Scheinowitz M et al. Obese adults with primary growth hormone resistance (Laron Syndrome) have normal endothelial function. Growth Horm IGF Res 2007; 17: 165–170.
- 30. Shevah O, Laron Z. Patients with congenital deficiency of IGF-I seem protecte from the development of malignancies: a preliminary report. Growth Horm IGF Res 2007; 17: 54–57.
- 31. Steuerman R, Shevah O, Laron Z. Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol 2011; 164: 485–489.
- 32. Westbrook R, Bonkowski MS, Strader AD et al. Alterations in oxygen consumption, respiratory quotient, and heat production in long-lived GHRKO and Ames dwarf mice, and short-lived bGH transgenic mice. J Gerontol A Biol Sci Med Sci 2009; 64: 443–451.
- 33. Heiman M, Tinsley F, Mattison J et al. Body composition of prolactin-, growth hormone-, and thyrotropin-deficient Ames dwarf mice. Endocrine 2003; 20: 149–154.
- 34. Bonkowski MS, Pamenter RW, Rocha JS et al. Long-lived growth hormone receptor knockout mice show a delay in age-related changes of body composition and bone characteristics. J Gerontol A Biol Sci Med Sci 2006; 61: 562–567.
- 35. Berryman DE, List EO, Palmer AJ et al. Two-year body composition analyses of long-lived GHR null mice. J Gerontol A Biol Sci Med Sci 2010; 65: 31–40.
- 36. Koizumi A WY, Tuskada M, Kayo T et al. A tumor preventive effect of dietary restriction is antagonized by a high housing temperature through deprivation of torpor. Mech Ageing Dev 1996; 92: 67–82.
- 37. Franceschi C, Olivieri F, Marchegiani F et al. Genes involved in immune response/inflammation, IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians. Mech Ageing Dev 2005; 126: 351–361.
- 38. Finch CE, Crimmins EM. Inflammatory exposure and historical changes in human life-spans. Science 2004; 305: 1736–1739.
- 39. Deepak D DC, Javadpour M, Clark D, Perry Y, Pinkney J, Macfarlane IA. The influence of growth hormone replacement on peripheral inflammatory and cardiovascular risk markers in adults with severe growth hormone deficiency. Growth Horm IGF Res 2010; 20: 220–225.
- 40. Yi C CY, Mao SH, Liu H et al. Recombinant human growth hormone improves survival and protects against acute lung injury in murine Staphylococcus aureus sepsis. Inflamm Res 2009; 58: 855–862.
- 41. Wang Z, Masternak MM, Al-Regaiey KA et al. Adipocytokines and the regulation of lipid metabolism in growth hormone transgenic and calorie-restricted mice. Endocrinology 2007; 148: 2845–2853.
- 42. Gaspari S, Marcovecchio ML, Breda L et al. Growth in juvenile idiopathic arthritis: the role of inflammation. Clin Exp Rheumatol 2011; 29: 104–110.
- 43. Chen Y, Sood S, Krishnamurthy VM et al. Endotoxin-induced growth hormone resistance in skeletal muscle. Endocrinology 2009; 150: 3620–3626.
- 44. Berryman DE, List EO, Coschigano KT et al. Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Horm IGF Res 2004; 14: 309–318.
- 45. Wang Z, Al-Regaiey KA, Masternak MM et al. Adipocytokines and lipid levels in Ames dwarf and caloric restricted mice. J Gerontol A Biol Sci Med Sci 2006; 61A: 323–331.
- 46. Muzumdar R, Allison DB, Huffman DM et al. Visceral adipose tissue modulates mammalian longevity. Aging Cell 2008; 7: 438–440.
- 47. Masternak MM, Bartke A, Wang F et al. Metabolic effects of intra-abdominal fat in GHRKO mice. Aging Cell 2012; 11: 73–81.
- 48. Dhahbi J, Li X, Tran T et al. Circulating blood leukocyte gene expression profiles: Effects of the Ames dwarf mutation on pathways related to immunity and inflammation. Experimental Gerontology 2007; 42: 772–788.
- 49. Ratajczak MZ, Zuba-Surma EK, Wysoczynski M et al. Hunt for pluripotent stem cell–regenerative medicine search for almighty cell. Journal of autoimmunity 2008; 30: 151–162.
- 50. D’Ippolito G, Diabira S, Howard GA et al. Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. Journal of Cell Science 2004; 117: 2971–2981.
- 51. Jiang Y, Jahagirdar BN, Reinhardt RL et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418: 41–49.
- 52. Beltrami AP, Cesselli D, Bergamin N et al. Multipotent cells can be generated in vitro from several adult human organs (heart, liver and bone marrow). Blood 2007; 110: 3438–3446.
- 53. Kucia M, Reca R, Campbell F et al. A population of very small embryonic-like (VSEL) CXCR4+ SSEA-1+ Oct-4+ stem cells identified in adult bone marrow. Leukemia 2006; 20: 857–869.
- 54. Kucia M, Wysoczynski M, Ratajczak J et al. Identification of very small embryonic like (VSEL) stem cells in bone marrow. Cell and Tissue Research 2008; 331: 125–134.
- 55. Ratajczak J, Wysoczynski M, Zuba-Surma E et al. Adult murine bone marrow-derived very small embryonic-like stem cells differentiate into the hematopoietic lineage after coculture over OP9 stromal cells. Exp Hematol 2011; 39: 225–237.
- 56. Taichman RS, Wang Z, Shiozawa Y et al. Prospective identification and skeletal localization of cells capable of multilineage differentiation in vivo. Stem Cells Dev 2010; 19: 1557–70.
- 57. Ratajczak MZ, Zuba-Surma EK, Shin D-M et al. Very small embryonic-like (VSEL) stem cells in adult organs and their potential role in rejuvenation of tissues and longevity. Experimental Gerontology 2008; 43: 1009–1017.
- 58. Ratajczak MZ, Shin DM, Liu R et al. Very small embryonic/epiblast-like stem cells (VSELs) and their potential role in aging and organ rejuvenation--an update and comparison to other primitive small stem cells isolated from adult tissues. Aging 2012; 4: 235–246.
- 59. Shin DM, Zuba-Surma EK, Wu W et al. Novel epigenetic mechanisms that control pluripotency and quiescence of adult bone marrow-derived Oct4+ very small embryonic-like stem cells. Leukemia 2009; 23: 2042–2051.
- 60. Ratajczak J, Shin DM, Wan W et al. Higher number of stem cells in the bone marrow of circulating low Igf-1 level Laron dwarf mice--novel view on Igf-1, stem cells and aging. Leukemia 2011; 25: 729–733.
- 61. Kucia M, Masternak M, Liu R et al. The negative effect of prolonged somatotrophic/insulin signaling on an adult bone marrow-residing population of pluripotent very small embryonic-like stem cells (VSELs). Age (Dordr) 2012. [Epub ahead of print]
- 62. Kucia M, Shin DM, Liu R et al. Reduced number of VSELs in the bone marrow of growth hormone transgenic mice indicates that chronically elevated Igf1 level accelerates age-dependent exhaustion of pluripotent stem cell pool: a novel view on aging. Leukemia 2011; 25: 1370–1374.
- 63. Patronek GJ, Waters DJ, Glickman LT. Comparative longevity of pet dogs and humans: implications for gerontology research. J Gerontol A Biol Sci Med Sci 1997; 52A: B171–B178.
- 64. Paradis MR. Demographics of health and disease in the geriatric horse. Vet Clin North Am Equine Pract 2002; 18: 391–401.
- 65. Samaras TT. Human body size and the laws of scaling: physiological, performance, growth, longevity and ecological ramifications. Nova Science Publishers, Inc., Hauppauge, N.Y. 2007.
- 66. Vergara M, Smith-Wheelock M, Harper JM et al. Hormone-treated Snell dwarf mice regain fertility but remain long lived and disease resistant. J Gerontol A Biol Sci Med Sci 2004; 59: 1244–1250.
- 67. Panici JA, Harper JM, Miller RA et al. Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long-lived mutant mice. FASEB J 2010; 24: 5073–5079.
- 68. Kopchick JJ, Andry JM. Growth hormone (GH), GH receptor, and signal transduction. Mol Genet Metab 2000; 71: 293–314.
- 69. Sun L SAA, Miller RA, Harper JM. Life-span extension in mice by preweaning food restriction and by methionine restriction in middle-age. J Gerontol A Biol Sci Med Sci 2009; 64: 711–722.
- 70. Sonntag WE, Carter CS, Ikeno Y et al. Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span. Endocrinology 2005; 146: 2920–2932.
- 71. Hoy WE, Rees M, Kile E et al. A new dimension to the Barker hypothesis: low birthweight and susceptibility to renal disease. Kidney Int 1999; 56: 1072–1077.
- 72. Roseboom TJ, van der Meulen JH, Osmond C et al. Adult survival after prenatal exposure to the Dutch famine 1944-45. Paediatr Perinat Epidemiol 2001; 15: 220–225.
![](https://journals.viamedica.pl/plugins/generic/popups/images/icons/close.png)