Abstract
The role of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in normal brain function is not well understood. Studies looking at cognition in humans with GH deficiency have produced controversial results. Experiments in which GH is administered to rodents have shown an apparent improvement in learning and memory. However, studies in which GH deficient or resistant mice were tested in learning and memory tasks reveal that these animals have normal cognitive performance and that their neural function does not deteriorate with age at the same rate as their normal siblings. Further research into this phenomenon revealed that these animals have elevated GH and IGF-1 expression in the hippocampus compared to normal animals. Additional studies with GH deficient and resistant mice suggested that these mutants experience a delay in age-related decline in locomotor activity and exploratory behavior. Data indicate that GH/IGF-1 deficiency and resistance do not impair neural function and instead may offer some degree of protection that results in delayed cognitive and motor aging.
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Abbreviations
- GH:
-
growth hormone
- IGF-1:
-
insulin-like growth factor-1
- GHRKO:
-
GH receptor knockout
- PRL:
-
prolactin
- TSH:
-
thyroid stimulating hormone
References
Abbot D, Rotnem D, Genel M et al (1982) Cognitive and emotional functioning in hypopituitary short statured children. Schizophr Bull 8:310–319
Almkvist O, Thoren M, Saaf M et al (1986) Effects of growth hormone substitution on mental performance in adults with growth hormone deficiency: a pilot study. Psychoneuroendocrinology 11:347–352
Balbis A, Dellacha JM, Calandra RS et al (1992) Down regulation of masked and unmasked insulin receptors in the liver of transgenic mice expressing bovine growth hormone gene. Life Sci 51:771–778
Bartke A (1964) Histology of the anterior hypophysis, thyroid and gonads of two types of dwarf mice. Anat Rec 149:225–235
Bartke A, Cecim M, Tang K et al (1994) Neuroendocrine and reproductive consequences of overexpression of growth hormone in transgenic mice. Proc Soc Exp Biol Med 206:345–359
Bartke A, Coschigano K, Kopchick J et al (2001) Genes that prolong life: relationships of growth hormone and growth to aging and life span. J Gerontol 56A: B340–B349
Baum HBA, Katznelson L, Sherman JC et al (1998) Effects of physiological growth hormone (GH) therapy on cognition and quality of life in patients with adult-onset GH deficiency. J Clin Endocrinol Metab 83:3184–3189
Binnerts A, Swart GR, Wilson JHP et al (1992) The effect of growth hormone administration in growth hormone deficient adults on bone, protein, carbohydrate and lipid homeostasis as well as on body composition. Clin Endocrinol 37:79–87
Borg KE, Brown-Borg HM, Bartke A (1995) Assessment of the primary adrenal cortical and pancreatic hormone basal levels in relation to plasma glucose and age in the unstressed Ames dwarf mice. Proc Soc Exp Biol Med 210:126–133
Brown-Borg HM, Rakoczy SG (2000) Catalase expression in delayed and premature aging mouse models. Exp Gerontol 35:199–212
Brown-Borg HM, Borg KE, Meliska CJ et al (1996) Dwarf mice and the aging process. Nature 384:33
Brown-Borg HM, Bode AM, Bartke A (1999) Antioxidative mechanisms and plasma growth hormone levels. Endocrine 11:41–48
Burman P, Broman JE, Hetta J et al (1995) Quality of life in adults with growth hormone (GH) deficiency: response to treatment with recombinant human GH in a placebo-controlled 21-month trial. J Clin Endocrinol Metab 80:3585–3590
Cecim M, Alvarez-Sanz M, Van De Kar L et al (1996) Increased plasma corticosterone levels in bovine growth hormone (bGH) transgenic mice: effect of ACTH, GH and IGF-1 on in vitro adrenal corticosterone production. Trans Res 5:187–192
Coschigano KT, Clemmons D, Bellush LL et al (2000) Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 14: 2608–2613
Cullen KJ, Yee D, Sly WS et al (1990) Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res 50:48–50
Dean HJ, McTaggart TL, Fish DG et al (1985) The educational, vocational, and marital status of growth hormone-deficient adults treated with growth hormone during childhood. Am J Dis Child 139:1105–1110
Degerblad M, Almkvist O, Grunditz R et al (1990) Physical and psychological capabilities during substitution therapy with recombinant growth hormone in adults with growth hormone deficiency. Acta Endocrinol 123:185–193
Deijen JB, de Boer H, Blok GJ et al (1996) Cognitive impairments and mood disturbances in growth hormone deficient men. Psychoneuroendocrinology 21: 313–322
Deijen JB, de Boer H, van der Veen EA (1998) Cognitive changes during growth hormone replacement in adult men. Psychoneuroendocrinology 23:45–55
Drotar D, Owens R, Gotthold J (1980) Personality adjustment of children and adolescents with hypopituitarism. Child Psychiatry Hum Dev 11:59–66
Flurkey K, Papaconstantinou J, Miller RA et al (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
Forster MJ, Dubey A, Dawson KM et al (1996) Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Proc Natl Acad Sci USA 93:4765–4769
Frankel JJ, Laron Z (1968) Psychological aspects of pituitary insufficiency in children and adolescents with special reference to growth hormone. Isr J Med Sci 4:953–961
French RA, Broussard SR, Meier WA et al (2002) Age-associated loss of bone marrow hematopoietic cells is reversed by GH and accompanies thymic reconstitution. Endocrinology 143:690–699
Frisch H, Hausler G, Lindenbauer S et al (1990) Psychological aspects in children and adolescents with hypopituitarism. Acta Paediatr Scand 79:644–651
Galatzer A, Aran O, Beit-Halachmi N et al (1987) Rehabilitation status of young adults with hGH deficiency after termination of therapy. Pediatr Adolesc Endocrinol 16:257–267
Galatzer A, Aran O, Nagelberg J et al (1993) Cognitive and psychosocial functioning of young adults with Laron syndrome. In: Laron Z, Parks JS (eds) Lessons from Laron syndrome (LS) 1996–1992. Karger, Basel, pp 53–60
Guevara-Aguirre J, Rosenbloom AL (1993) Psychosocial adaptation of Ecuadorian patients with growth hormone receptor deficiency/Laron syndrome. Pediatr Adolesc Endocrinol 24:61–64
Hauck S, Bartke A (2000) Effects of growth hormone on hypothalamic catalase and Cu/Zn superoxide dismutase. Free Radic Biol Med 28:970–978
Holmes CS, Thompson RG, Hayford JT (1984) Factors related to grade retention in children with short stature. Child Care Health Dev 10:199–210
Jorgensen JOL, Pedersen SA, Thuesen L et al (1991) Long-term growth hormone treatment in growth hormone deficient adults. Acta Endocrinol 125:449–453
Kalu DN, Orhii PB, Chen C et al (1998) Aged-rodent models of long-term growth hormone therapy-lack of deleterious effect on longevity. J Biol Sci 53:B452–B463
Khansari DN, Gustad T (1991) Effects of long-term, low-dose growth hormone therapy on immune function and life expectancy of mice. Mech Ageing Dev 57:87–100
Kinney BA, Coschigano KT, Kopchick JJ et al (2001a) Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice. Physiol Behav 72:653–660
Kinney BA, Meliska CJ, Steger RW et al (2001b) Evidence that Ames Dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters. Horm Behav 39:277–284
Kinney-Forshee BA, Kinney NE, Steger RW et al (2004) Could a deficiency in growth hormone signaling be beneficial to the aging brain? Physiol Behav 80:589–594
Kranzler JH, Rosenbloom AL, Martinez V et al (1998) Normal intelligence with severe insulin-like growth factor I deficiency due to growth hormone receptor deficiency: a controlled study in a genetically homogeneous population. J Clin Endocrinol Metab 83: 1953–1958
Laron Z (1999) The essential role of IGF-1: lessons from the long-term study and treatment of children and adults with Laron syndrome. J Clin Endocrinol Metab 84:4397–4404
Laron Z (2005) Do deficiencies in growth hormone and insulin-like growth factor-1 (IGF-1) shorten or prolong longevity? Mech Ageing Dev 126:305–307
Marcus R, Butterfield G, Holloway L et al (1990) Effects of short-term administration of recombinant human growth hormone to elderly people. J Endocrinol Metab 70:519–527
Mattson MP, Maudsley S, Martin B (2004) A neural signaling triumvirate that influences ageing and age-related disease: insulin/IGF-1, BDNF and serotonin. Age Res Rev 3:445–464
McGauley GA, Cuneo RC, Salomon F et al (1990) Psychological well-being before and after growth hormone treatment in adults with growth hormone deficiency. Horm Res 33:52–54
Meites J (1988) Neuroendocrine biomarkers of aging in the rat. Exp Gerontol 23:349–358
Meyer-Bahlburg HFL, Feinman JA, MacGillivray MH et al (1978) Growth hormone deficiency, brain development, and intelligence. Am J Dis Child 132:565–572
Money J, Drash PW, Lewis V (1967) Dwarfism and hypopituitarism: statural retardation without mental retardation. Am J Ment Defic 72:122–126
Moon HD, Simpson ME, Li CH et al (1950) Neoplasm in rats treated with pituitary growth hormone. I. Pulmonary and lymphatic tissues. Cancer Res 10: 297–308
Moscrip TD, Ingram DK, Lane MA et al (2000) Locomotor activity in female rhesus monkeys: assessment of age and calorie restriction effects. J Gerontol 55: B373–B380
Muller EE, Cella SG, De Gennaro Colonna V et al (1993) Aspects of the neuroendocrine control of growth hormone secretion in ageing mammals. J Reprod Fertil 46:99–114
Miyamoto M, Kryota Y, Nishiyama M, Nagaoka A (1992) Senescence-acceleratedmouse (SAM): age-related reduced anxiety-like behavior in the SAM-P/8strain. Physiol Behav 51:979–985
Pendergast WR, Li Y, Jiang D et al (1993) Decrease in cellular replicative potential in “giant” mice transfected with the bovine growth hormone gene correlates to shortened life span. J Cell Physiol 156:96–103
Ranke MB (1987) A note on adults with growth hormone deficiency. Acta Paediatr Scand 331:80–82
Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG et al (1996) The little women of Loja—growth hormone-receptor deficiency in an inbred population of southern Ecuador. N Engl J Med 323:1367–1374
Rudman D (1985) Growth hormone, body composition and aging. J Am Geriatr Soc 33:800–807
Rudman D, Feller G, Nagraj HS et al (1990) Effects of human growth hormone in men over 60 years old. N Engl J Med 323:1–6
Sanz A, Bartke A, Barja G (2002) Long-lived Ames dwarf mice: oxidative damage to mitochondrial DNA in heart and brain. J Am Aging 25:119–122
Sartorio A, Peri G, Molinari E et al (1986) The psychosocial outcome of adults with growth hormone deficiency. Acta Med Auxol 18:123–128
Sartorio A, Molinari E, Riva G et al (1995) Growth hormone treatment in adults with childhood onset growth hormone deficiency: effects on psychological capabilities. Horm Res 44:6–11
Sartorio A, Conti A, Molinari E et al (1996) Growth, growth hormone and cognitive functions. Horm Res 45:23–29
Schneider-Rivas S, Rivas-Arancibia S, Vazquez-Pereyra F et al (1995) Modulation of long-term memory and extinction responses induced by growth hormone (GH) and growth hormone releasing hormone (GHRH) in rats. Life Sci 56:PL433–PL441
Shi L, Linville MC, Tucker EW et al (2005) Differential effects of aging and insulin-like growth factor-1 on synapses in CA1 of rat hippocampus. Cereb Cortex 15:571–577
Sonntag WE, Lynch C, Thornton P et al (2000) The effects of growth hormone and IGF-1 deficiency on cerebrovascular and brain ageing. J Anat 4:575–585
Sornson MW, Wu W, Dasen JS et al (1996) Pituitary lineage determination by the prophet of pit-1 homeodomain factor defective in Ames dwarfism. Nature 384:327–333
Stabler B (1991) Growth hormone insufficiency during childhood has implications for later life. Acta Paediatr Scand 377:9–13
Steger RW, Bartke A, Cecim M (1993a) Premature ageing in transgenic mice expressing different growth hormone genes. J Reprod Fertil 46:61–75
Steger RW, Bartke A, Yun JS et al (1993b) Neuroendocrine function in transgenic mice with phosphoenolpyruvate carboxykinase/human growth hormone (PEPCK/hGH) hybrid gene and very high peripheral levels of hGH. Transgene 1:19–26
Steinhausen H, Stahnke N (1976) Psychoendocrinological studies in dwarfed children and adolescents. Arch Dis Child 51:778–783
Steinhausen HC, Stahnke N (1977) Negative impact of growth-hormone deficiency on psychological functioning in dwarfed children and adolescents. Euro J Pediatr 126:263–270
Steinhausen HC, Wefers D (1976) Intelligence structure and personality in various types of physical handicap in childhood and adolescence. Neuropaediatrie 7:313–321
Sun LY, Al-Regaiey K, Masternak MM et al (2005a) Local expression of GH and IGF-1 in the hippocampus of GH-deficient long-lived mice. Neurobiol Aging 26:929–937
Sun LY, Evans MS, Hsieh J et al (2005b) Increased neurogenesis in dentate gyrus of long-lived Ames dwarf mice. Endocrinology 146:1138–1144
Takano K, Tanaka T, Saito T, Committee for the Study Group of Adult GH Deficiency (1994) Psychosocial adjustment in a large cohort of adults with growth hormone deficiency treated with growth hormone in childhood: summary of a questionnaire survey. Acta Paediatr Scand Suppl 399:16–19
Thornton PL, Ingram RL, Sonntag WE (2000) Chronic [d-Ala2]-growth hormone-releasing hormone administration attenuates age-related deficits in spatial memory. J Gerontol 55:B106–B112
Vance ML (1990) Growth hormone for the elderly? N Engl J Med 323:52–54
Vicens-Calvert E, Bargada M, Potau N et al (1993) Psychosocial status of adults with growth hormone deficiency. Acta Endocrinol 128:71
Weinert D, Waterhouse J (1999) Daily activity and body temperature rhythms do not change simultaneously with age in laboratory mice. Physiol Behav 66:605–612
Zhou Y, Xu BC, Maheshwari HG et al (1997) A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (The Laron mouse). Proc Natl Acad Sci USA 94:13215–13220
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Forshee, B.A. The aging brain: is function dependent on growth hormone/insulin-like growth factor-1 signaling?. AGE 28, 173–180 (2006). https://doi.org/10.1007/s11357-006-9005-9
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DOI: https://doi.org/10.1007/s11357-006-9005-9