Abstract
Experimental, clinical, and epidemiological findings support the concept of developmental origins of health and disease (DOHAD), suggesting that early-life hormonal influences during a sensitive period around adolescence have a powerful impact on cancer morbidity later in life. The endocrine changes that occur during puberty are highly conserved across mammalian species and include dramatic increases in circulating GH and IGF-1 levels. Importantly, patients with developmental IGF-1 deficiency due to GH insensitivity (Laron syndrome) do not develop cancer during aging. Rodents with developmental GH/IGF-1 deficiency also exhibit significantly decreased cancer incidence at old age, marked resistance to chemically induced carcinogenesis, and cellular resistance to genotoxic stressors. Early-life treatment of GH/IGF-1-deficient mice and rats with GH reverses the cancer resistance phenotype; however, the underlying molecular mechanisms remain elusive. The present study was designed to test the hypothesis that developmental GH/IGF-1 status impacts cellular DNA repair mechanisms. To achieve that goal, we assessed repair of γ-irradiation-induced DNA damage (single-cell gel electrophoresis/comet assay) and basal and post-irradiation expression of DNA repair-related genes (qPCR) in primary fibroblasts derived from control rats, Lewis dwarf rats (a model of developmental GH/IGF-1 deficiency), and GH-replete dwarf rats (GH administered beginning at 5 weeks of age, for 30 days). We found that developmental GH/IGF-1 deficiency resulted in persisting increases in cellular DNA repair capacity and upregulation of several DNA repair-related genes (e.g., Gadd45a, Bbc3). Peripubertal GH treatment reversed the radiation resistance phenotype. Fibroblasts of GH/IGF-1-deficient Snell dwarf mice also exhibited improved DNA repair capacity, showing that the persisting influence of peripubertal GH/IGF-1 status is not species-dependent. Collectively, GH/IGF-1 levels during a critical period during early life determine cellular DNA repair capacity in rodents, presumably by transcriptional control of genes involved in DNA repair. Because lifestyle factors (e.g., nutrition and childhood obesity) cause huge variation in peripubertal GH/IGF-1 levels in children, further studies are warranted to determine their persisting influence on cellular cancer resistance pathways.
Similar content being viewed by others
References
Alderete TL, Byrd-Williams CE, Toledo-Corral CM, Conti DV, Weigensberg MJ, Goran MI (2011) Relationships between igf-1 and igfbp-1 and adiposity in obese african-american and latino adolescents. Obesity (Silver Spring) 19:933–938
Bailey-Downs LC, Sosnowska D, Toth P, Mitschelen M, Gautam T, Henthorn JC, Ballabh P, Koller A, Farley JA, Sonntag WE, Csiszar A, Ungvari Z (2012a) Growth hormone and igf-1 deficiency exacerbate high-fat diet-induced endothelial impairment in obese Lewis dwarf rats: implications for vascular aging. J Gerontol A Biol Sci Med Sci 67:553–564
Bailey-Downs LC, Mitschelen M, Sosnowska D, Toth P, Pinto JT, Ballabh P, Valcarcel-Ares MN, Farley J, Koller A, Henthorn JC, Bass C, Sonntag WE, Ungvari Z, Csiszar A (2012b) Liver-specific knockdown of igf-1 decreases vascular oxidative stress resistance by impairing the nrf2-dependent antioxidant response: a novel model of vascular aging. J Gerontol Biol Med Sci 67:313–329
Ballerini MG, Ropelato MG, Domene HM, Pennisi P, Heinrich JJ, Jasper HG (2004) Differential impact of simple childhood obesity on the components of the growth hormone-insulin-like growth factor (igf)-igf binding proteins axis. J Pediatr Endocrinol Metab 17:749–757
Barreto G, Schafer A, Marhold J, Stach D, Swaminathan SK, Handa V, Doderlein G, Maltry N, Wu W, Lyko F, Niehrs C (2007) Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 445:671–675
Berryman DE, Christiansen JS, Johannsson G, Thorner MO, Kopchick JJ (2008) Role of the gh/igf-1 axis in lifespan and healthspan: lessons from animal models. Growth Hormon IGF Res 18:455–471
Bidlingmaier M, Friedrich N, Emeny RT, Spranger J, Wolthers OD, Roswall J, Korner A, Obermayer-Pietsch B, Hubener C, Dahlgren J, Frystyk J, Pfeiffer AF, Doering A, Bielohuby M, Wallaschofski H, Arafat AM (2014) Reference intervals for insulin-like growth factor-1 (igf-i) from birth to senescence: results from a multicenter study using a new automated chemiluminescence igf-i immunoassay conforming to recent international recommendations. J Clin Endocrinol Metab 99:1712–1721
Bokov AF, Lindsey ML, Khodr C, Sabia MR, Richardson A (2009) Long-lived Ames dwarf mice are resistant to chemical stressors. J Gerontol A Biol Sci Med Sci 64:819–827
Bouhours-Nouet N, Gatelais F, Boux de Casson F, Rouleau S, Coutant R (2007) The insulin-like growth factor-i response to growth hormone is increased in prepubertal children with obesity and tall stature. J Clin Endocrinol Metab 92:629–635
Brown-Borg HM, Borg KE, Meliska CJ, Bartke A (1996) Dwarf mice and the ageing process. Nature 384:33
Brown-Borg HM, Rakoczy SG, Sharma S, Bartke A (2009) Long-living growth hormone receptor knockout mice: potential mechanisms of altered stress resistance. Exp Gerontol 44:10–19
Burgers AM, Biermasz NR, Schoones JW, Pereira AM, Renehan AG, Zwahlen M, Egger M, Dekkers OM (2011) Meta-analysis and dose-response metaregression: circulating insulin-like growth factor i (igf-i) and mortality. J Clin Endocrinol Metab 96:2912–2920
Burt Solorzano CM, McCartney CR (2010) Obesity and the pubertal transition in girls and boys. Reproduction 140:399–410
Carter CS, Ramsey MM, Sonntag WE (2002a) A critical analysis of the role of growth hormone and igf-1 in aging and lifespan. Trends Genet 18:295–301
Carter CS, Ramsey MM, Ingram RL, Cashion AB, Cefalu WT, Wang ZQ, Sonntag WE (2002b) Models of growth hormone and igf-1 deficiency: applications to studies of aging processes and life-span determination. J Gerontol A Biol Sci Med Sci 57:B177–B188
Charlton HM, Clark RG, Robinson IC, Goff AE, Cox BS, Bugnon C, Bloch BA (1988) Growth hormone-deficient dwarfism in the rat: a new mutation. J Endocrinol 119:51–58
Csiszar A, Labinskyy N, Zhao X, Hu F, Serpillon S, Huang Z, Ballabh P, Levy RJ, Hintze TH, Wolin MS, Austad SN, Podlutsky A, Ungvari Z (2007) Vascular superoxide and hydrogen peroxide production and oxidative stress resistance in two closely related rodent species with disparate longevity. Aging Cell 6:783–797
Csiszar A, Labinskyy N, Podlutsky A, Kaminski PM, Wolin MS, Zhang C, Mukhopadhyay P, Pacher P, Hu F, de Cabo R, Ballabh P, Ungvari Z (2008) Vasoprotective effects of resveratrol and sirt 1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations. Am J Physiol Heart Circ Physiol 294:H2721–H2735
Csiszar A, Tucsek Z, Toth P, Sosnowska D, Gautam T, Koller A, Deak F, Sonntag WE, Ungvari ZI. Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in beta-amyloid generation and ad. Am J Physiol Heart Circ Physiol. 2013
D'Costa AP, Ingram RL, Lenham JE, Sonntag WE (1993) The regulation and mechanisms of action of growth hormone and insulin-like growth factor 1 during normal ageing. J Reprod Fertil Suppl 46:87–98
Deak F, Sonntag WE (2012) Aging, synaptic dysfunction, and insulin-like growth factor (igf)-1. J Gerontol A Biol Sci Med Sci 67:611–625
Dominick G, Bowman J, Li X, Miller RA, Garcia GG. Mtor regulates the expression of DNA damage response enzymes in long-lived snell dwarf, ghrko, and pappa-ko mice. Aging Cell 2016
Flurkey K, Papaconstantinou J, Miller RA, Harrison DE (2001) Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A 98:6736–6741
Garnett SP, Hogler W, Blades B, Baur LA, Peat J, Lee J, Cowell CT (2004) Relation between hormones and body composition, including bone, in prepubertal children. Am J Clin Nutr 80:966–972
Gesing A, Wiesenborn D, Do A, Menon V, Schneider A, Victoria B, Stout MB, Kopchick JJ, Bartke A, Masternak MM. A long-lived mouse lacking both growth hormone and growth hormone receptor: A new animal model for aging studies. J Gerontol A Biol Sci Med Sci 2016
Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, de Cabo R, Cohen P, Longo VD (2011) Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 3:70ra13
Harper JM, Salmon AB, Leiser SF, Galecki AT, Miller RA (2007) Skin-derived fibroblasts from long-lived species are resistant to some, but not all, lethal stresses and to the mitochondrial inhibitor rotenone. Aging Cell 6:1–13
Harvey M, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A, Donehower LA (1993) Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nat Genet 5:225–229
Haslam SZ, Schwartz RC (2011) Is there a link between a high-fat diet during puberty and breast cancer risk? Women's Health (Lond Engl) 7:1–3
Hollander MC, Sheikh MS, Bulavin DV, Lundgren K, Augeri-Henmueller L, Shehee R, Molinaro TA, Kim KE, Tolosa E, Ashwell JD, Rosenberg MP, Zhan Q, Fernandez-Salguero PM, Morgan WF, Deng CX, Fornace AJ Jr (1999) Genomic instability in gadd45a-deficient mice. Nat Genet 23:176–184
Hollander MC, Kovalsky O, Salvador JM, Kim KE, Patterson AD, Haines DC, Fornace AJ Jr (2001) Dimethylbenzanthracene carcinogenesis in gadd45a-null mice is associated with decreased DNA repair and increased mutation frequency. Cancer Res 61:2487–2491
Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y (2003) Igf-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421:182–187
Hsieh CC, Papaconstantinou J (2009) Dermal fibroblasts from long-lived Ames dwarf mice maintain their in vivo resistance to mitochondrial generated reactive oxygen species (ros). Aging (Albany NY) 1:784–802
Ikeno Y, Bronson RT, Hubbard GB, 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
Johnson KJ, Springer NM, Bielinsky AK, Largaespada DA, Ross JA (2009) Developmental origins of cancer. Cancer Res 69:6375–6377
Jung HJ, Kim EH, Mun JY, Park S, Smith ML, Han SS, Seo YR (2007) Base excision DNA repair defect in gadd45a-deficient cells. Oncogene 26:7517–7525
Labinskyy N, Mukhopadhyay P, Toth J, Szalai G, Veres M, Losonczy G, Pinto JT, Pacher P, Ballabh P, Podlutsky A, Austad SN, Csiszar A, Ungvari Z (2009) Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus. Am J Physiol Heart Circ Physiol 296:H946–H956
Leiser SF, Miller RA (2010) Nrf2 signaling, a mechanism for cellular stress resistance in long-lived mice. Mol Cell Biol 30:871–884
Leiser SF, Salmon AB, Miller RA (2006) Correlated resistance to glucose deprivation and cytotoxic agents in fibroblast cell lines from long-lived pituitary dwarf mice. Mech Ageing Dev 127:821–829
List EO, Berryman DE, Funk K, Jara A, Kelder B, Wang F, Stout MB, Zhi X, Sun L, White TA, LeBrasseur NK, Pirtskhalava T, Tchkonia T, Jensen EA, Zhang W, Masternak MM, Kirkland JL, Miller RA, Bartke A, Kopchick JJ (2014) Liver-specific gh receptor gene-disrupted (lighrko) mice have decreased endocrine igf-i, increased local igf-i, and altered body size, body composition, and adipokine profiles. Endocrinology 155:1793–1805
Moore T, Carbajal S, Beltran L, Perkins SN, Yakar S, Leroith D, Hursting SD, Digiovanni J (2008) Reduced susceptibility to two-stage skin carcinogenesis in mice with low circulating insulin-like growth factor i levels. Cancer Res 68:3680–3688
Murakami S, Salmon A, Miller RA (2003) Multiplex stress resistance in cells from long-lived dwarf mice. FASEB J 17:1565–1566
Olivo-Marston SE, Hursting SD, Lavigne J, Perkins SN, Maarouf RS, Yakar S, Harris CC (2009) Genetic reduction of circulating insulin-like growth factor-1 inhibits azoxymethane-induced colon tumorigenesis in mice. Mol Carcinog 48:1071–1076
Olson LK, Tan Y, Zhao Y, Aupperlee MD, Haslam SZ (2010) Pubertal exposure to high fat diet causes mouse strain-dependent alterations in mammary gland development and estrogen responsiveness. Int J Obes 34:1415–1426
Ong K, Kratzsch J, Kiess W, Dunger D (2002) Circulating igf-i levels in childhood are related to both current body composition and early postnatal growth rate. J Clin Endocrinol Metab 87:1041–1044
Osborne CK, Bolan G, Monaco ME, Lippman ME (1976) Hormone responsive human breast cancer in long-term tissue culture: effect of insulin. Proc Natl Acad Sci U S A 73:4536–4540
Page MM, Salmon AB, Leiser SF, Robb EL, Brown MF, Miller RA, Stuart JA (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
Panici JA, Harper JM, Miller RA, Bartke A, Spong A, Masternak MM (2010) Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long-lived mutant mice. FASEB J 24:1–7
Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4:505–518
Ramsey MM, Ingram RL, Cashion AB, Ng AH, Cline JM, Parlow AF, Sonntag WE (2002) Growth hormone-deficient dwarf animals are resistant to dimethylbenzanthracine (dmba)-induced mammary carcinogenesis. Endocrinology 143:4139–4142
Renehan AG, Zwahlen M, Minder C, O'Dwyer ST, Shalet SM, Egger M (2004) Insulin-like growth factor (igf)-i, igf binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363:1346–1353
Salmon AB, Murakami S, Bartke A, Kopchick J, Yasumura K, Miller RA (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
Salmon AB, Ljungman M, Miller RA (2008) Cells from long-lived mutant mice exhibit enhanced repair of ultraviolet lesions. J Gerontol A Biol Sci Med Sci 63:219–231
Sonntag WE, Lynch CD, Cefalu WT, Ingram RL, Bennett SA, Thornton PL, Khan AS (1999) Pleiotropic effects of growth hormone and insulin-like growth factor (igf)-1 on biological aging: inferences from moderate caloric-restricted animals. J Gerontol A Biol Sci Med Sci 54:B521–B538
Sonntag WE, Lynch C, Thornton P, Khan A, Bennett S, Ingram R (2000) The effects of growth hormone and igf-1 deficiency on cerebrovascular and brain ageing. J Anat 197(Pt 4):575–585
Sonntag WE, Ramsey M, Carter CS (2005a) Growth hormone and insulin-like growth factor-1 (igf-1) and their influence on cognitive aging. Ageing Res Rev 4:195–212
Sonntag WE, Carter CS, Ikeno Y, Ekenstedt K, Carlson CS, Loeser RF, Chakrabarty S, Lee S, Bennett C, Ingram R, Moore T, Ramsey M (2005b) Adult-onset growth hormone and insulin-like growth factor i deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span. Endocrinology 146:2920–2932
Sonntag WE, Csiszar A, de Cabo R, Ferrucci L, Ungvari Z (2012) Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian aging: progress and controversies. J Gerontol A Biol Sci Med Sci 67:587–598
Sonntag WE, Deak F, Ashpole N, Toth P, Csiszar A, Freeman W, Ungvari Z (2013) Insulin-like growth factor-1 in cns and cerebrovascular aging. Front Aging Neurosci 5:27
Sorensen K, Aksglaede L, Petersen JH, Andersson AM, Juul A (2012) Serum igf1 and insulin levels in girls with normal and precocious puberty. Eur J Endocrinol 166:903–910
Sun LY, Bartke A (2007) Adult neurogenesis in the hippocampus of long-lived mice during aging. J Gerontol A Biol Sci Med Sci 62:117–125
Sun LY, Al-Regaiey K, Masternak MM, Wang J, Bartke A (2005) Local expression of gh and igf-1 in the hippocampus of gh-deficient long-lived mice. Neurobiol Aging 26:929–937
Tarantini S, Giles CB, Wren JD, Ashpole NM, Valcarcel-Ares MN, Wei JY, Sonntag WE, Ungvari Z, Csiszar A (2016a) Igf-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering mirna-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis. Age (Dordr) 38:239–258
Tarantini S, Tucsek Z, Valcarcel-Ares M, Toth P, Gautam T, Giles C, Ballabh P, Wei Y, Wren J, Ashpole N, Sonntag W, Ungvari Z, Csiszar A (2016b) Circulating igf-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging. Age (Dordr) 38:273–289
Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S, Deak F, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2013) Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin ii-induced hypertension. J Cereb Blood Flow Metab 33:1732–1742
Toth P, Tucsek Z, Tarantini S, Sosnowska D, Gautam T, Mitschelen M, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2014a) Igf-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice. J Cereb Blood Flow Metab 34:1887–1897
Toth P, Tucsek Z, Tarantini S, Sosnowska D, Gautam T, Mitschelen M, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2014b) Igf-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice. J Cereb Blood Flow Metab 34(12):1887–1897
Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel-Ares NM, Menyhart A, Farkas E, Sonntag WE, Csiszar A, Ungvari Z (2015) Igf-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell 14:1034–1044
Tucsek Z, Toth P, Sosnowsk D, Gautam T, Mitschelen M, Koller A, Szalai G, Sonntag WE, Ungvari Z, Csiszar A. Obesity in aging exacerbates blood brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and alzheimer's disease J Gerontol Biol Med Sci. 2013: in press
Tucsek Z, Toth P, Tarantini S, Sosnowska D, Gautam T, Warrington JP, Giles CB, Wren JD, Koller A, Ballabh P, Sonntag WE, Ungvari Z, Csiszar A (2014) Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol A Biol Sci Med Sci 69:1339–1352
Ungvari Z, Orosz Z, Rivera A, Labinskyy N, Xiangmin Z, Olson S, Podlutsky A, Csiszar A (2007) Resveratrol increases vascular oxidative stress resistance. Am J Physiol 292:H2417–H2424
Ungvari Z, Gautam T, Koncz P, Henthorn JC, Pinto JT, Ballabh P, Yan H, Mitschelen M, Farley J, Sonntag WE, Csiszar A (2010) Vasoprotective effects of life span-extending peripubertal gh replacement in Lewis dwarf rats. J Gerontol A Biol Sci Med Sci 65:1145–1156
Ungvari Z, Sosnowska D, Podlutsky A, Koncz P, Sonntag WE, Csiszar A (2011) Free radical production, antioxidant capacity, and oxidative stress response signatures in fibroblasts from Lewis dwarf rats: effects of life span-extending peripubertal gh treatment. J Gerontol A Biol Sci Med Sci 66:501–510
Ungvari Z, Podlutsky A, Sosnowska D, Tucsek Z, Toth P, Deak F, Gautam T, Csiszar A, Sonntag WE (2013a) Ionizing radiation promotes the acquisition of a senescence-associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: role of increased DNA damage and decreased DNA repair capacity in microvascular radiosensitivity. J Gerontol A Biol Sci Med Sci 68:1443–1457
Ungvari Z, Sosnowska D, Mason JB, Gruber H, Lee SW, Schwartz TS, Brown MK, Storm NJ, Fortney K, Sowa J, Byrne AB, Kurz T, Levy E, Sonntag WE, Austad SN, Csiszar A, Ridgway I (2013b) Resistance to genotoxic stresses in Arctica islandica, the longest living noncolonial animal: is extreme longevity associated with a multistress resistance phenotype? J Gerontol A Biol Sci Med Sci 68:521–529
Vergara M, Smith-Wheelock M, Harper JM, Sigler R, Miller RA (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
Walker CL, Ho SM (2012) Developmental reprogramming of cancer susceptibility. Nat Rev Cancer 12:479–486
Warrington JP, Csiszar A, Johnson DA, Herman TS, Ahmad S, Lee YW, Sonntag WE (2011) Cerebral microvascular rarefaction induced by whole brain radiation is reversible by systemic hypoxia in mice. Am J Physiol Heart Circ Physiol 300:H736–H744
Warrington JP, Csiszar A, Mitschelen M, Lee YW, Sonntag WE (2012) Whole brain radiation-induced impairments in learning and memory are time-sensitive and reversible by systemic hypoxia. PLoS One 7:–e30444
Wu Y, Cui K, Miyoshi K, Hennighausen L, Green JE, Setser J, LeRoith D, Yakar S (2003) Reduced circulating insulin-like growth factor i levels delay the onset of chemically and genetically induced mammary tumors. Cancer Res 63:4384–4388
Yakar S, Pennisi P, Zhao H, Zhang Y, LeRoith D (2004) Circulating igf-1 and its role in cancer: lessons from the igf-1 gene deletion (lid) mouse. Novartis Found Symp 262:3–9 discussion 9-18, 265-268
Yan H, Mitschelen M, Toth P, Ashpole NM, Farley JA, Hodges EL, Warrington JP, Han S, Fung KM, Csiszar A, Ungvari Z, Sonntag WE (2014) Endothelin-1-induced focal cerebral ischemia in the growth hormone/igf-1 deficient Lewis dwarf rat. J Gerontol A Biol Sci Med Sci 69:1353–1362
Zhao Y, Tan YS, Aupperlee MD, Langohr IM, Kirk EL, Troester MA, Schwartz RC, Haslam SZ (2013) Pubertal high fat diet: effects on mammary cancer development. Breast Cancer Res 15:R100
Acknowledgement
This work was supported by grants from the American Heart Association (to MNVA, AC and ZU), the National Center for Complementary and Alternative Medicine (R01-AT006526 to ZU), the National Institute on Aging (R01-AG047879; R01-AG038747; 3P30AG050911-02S1 to AC, WES and ZU, AG019899 and AG024824 to RAM), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218 to AC), the National Institute of General Medical Sciences (UL1GM118991, TL4GM118992, and RL5GM118990 to AP and VP), the Arkansas Claude Pepper Older Americans Independence Center at University of Arkansas Medical Center (to ZU; P30 AG028718), the Oklahoma Center for the Advancement of Science and Technology (to AC, ZU), the Oklahoma IDeA Network for Biomedical Research Excellence (to AC), and the Reynolds Foundation (to ZU and AC) and by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103395 (to AP and KY). The content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIH.
Author contribution
AP, AC, and ZU designed research; MNVA, AP, KV, VP, EN, TG, and RAM performed experiments; AP, MNVA, AC, RAM, WES, and ZU analyzed and interpreted data; AP, AC, and ZU wrote the paper; MNVA, WES, RAM revised the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
About this article
Cite this article
Podlutsky, A., Valcarcel-Ares, M.N., Yancey, K. et al. The GH/IGF-1 axis in a critical period early in life determines cellular DNA repair capacity by altering transcriptional regulation of DNA repair-related genes: implications for the developmental origins of cancer. GeroScience 39, 147–160 (2017). https://doi.org/10.1007/s11357-017-9966-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11357-017-9966-x