Sci. Aging Knowl. Environ., 1 September 2004
Vol. 2004, Issue 35, p. pe33
[DOI: 10.1126/sageke.2004.35.pe33]


Not Wisely but Too Well: Aging as a Cost of Neuroendocrine Activity

Charles V. Mobbs

The author is in the Departments of Neuroscience and Geriatrics, Mt. Sinai School of Medicine, One Gustav Levy Place, Box 1065, New York, NY 10029, USA. E-mail: charles.mobbs{at}

Key Words: diabetes • glucocorticoids • glucose metabolism • neuroendocrine signaling • reproduction • stress


Although hormone secretion is regulated at the level of specific glands, a small number of neurons (located in the hypothalamus in mammals) ensure coordinated secretion of all hormones in response to environmental circumstances such as food availability. The hormones, the glands that secrete them, and the neurons that control their secretion together make up the "neuroendocrine system."

The idea that reduced glandular secretions would lead to physiological impairments and, eventually, death was among the earliest theories of aging. This notion continues to guide research examining the effects of aging on the many endocrine systems whose activities decrease with age (1; and see Hornsby Review). For example, reduced secretion of estradiol after the female menopause predisposes to osteoporosis (see "More Than a Hot Flash"), and age-related reduction in growth hormone (GH) secretion may cause loss of muscle mass and other age-related impairments in some elderly individuals (2). On the other hand, there is no evidence that increasing neuroendocrine activity or hormone levels can extend life span. On the contrary, evidence continues to accumulate that life span may in fact be reduced by neuroendocrine activity.

Indications that cumulative exposure to humoral substances drives the aging process came from studies in rats showing that the development of several age-related pathologies is delayed by hypophysectomy, the complete removal of the pituitary gland. Because the anterior pituitary secretes hormones that are required for the function of several other endocrine glands, including the thyroid, adrenal gland, and gonads, hypophysectomy causes the plasma concentration of many hormones to be reduced. A number of these studies reported that hypophysectomy slowed the rate of collagen cross-linking during aging (3-5), while later studies indicated that hypophysectomy delays age-correlated changes in kidney (6), muscle (7, 8), and ovary (9), as well as the development of gross pathologies and tumors (10). Under appropriate environmental conditions, hypophysectomy was even reported to extend rodent life span (10).

More recently, inactivation of pituitary function in mammals by genetic means has shown that pituitary secretions can accelerate aging (see Bartke Viewpoint, Quarrie Review, and "Power to the People"). The mouse Prop-1df mutation, which inactivates a transcription factor required for the development of several pituitary hormone-secreting cell types, increases life span in mice by more than 50% (11; and see Ames dwarf mice). Similarly, the Pit1dw mutation, which inactivates a different transcription factor needed for pituitary development, also increases murine life span (12; and see Snell dwarf mice). As shown in Fig. 1, the pituitary normally produces growth hormone (GH), which induces other tissues to produce insulin-like growth factor 1 (IGF-1), but these mice are deficient in GH and as a result exhibit abnormally low concentrations of IGF-1. Because mutations specifically compromising insulin/IGF-1 signaling pathways also increase life span, as described below, it is likely that hypophysectomy and the Prop-1df and Pit1dw mutations all affect life span by a reduction in GH and correspondingly reduced IGF-1 secretion. Mutations that selectively reduce GH secretion, however, such as the mouse Ghrhrlit/lit mutation, which inactivates the growth-hormone-releasing-hormone receptor (GHRHR; see Little mice), evince a smaller effect on life span than the Prop-1df and Pit1dw mutations (12). Therefore other hormones dependent on pituitary function, especially thyroid hormone, may also affect life span. From these studies we may conclude that activity of GH and other hormones restricts life span in mammals, and thus in part drives the aging process.

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Fig. 1. Regulation of insulin/IGF-1 signaling by the neuroendocrine system. The secretion of IGF-1 from liver is stimulated by GH, whose secretion in turn is stimulated by growth hormone-releasing hormone (GHRH) released by nutrition-stimulated hypothalamic neurons. Secretion of insulin is regulated by autonomic neurons whose activity is also regulated by nutrition-stimulated hypothalamic neurons. Insulin acting on fat cells causes the release of leptin and other adipose-derived hormone factors that can instruct the hypothalamus that nutritional stores are adequate, thereby closing the neuroendocrine loop regulating metabolic state. Inactivation of insulin receptors in fat cells increases life span, suggesting that insulin stimulates fat cells to release hypothetical toxic (or pro-aging) substances, which may be adipokines or other substances. This is consistent with data in invertebrates that, although insulin-like factors that limit life span derive from neurons, the effects on life span are mediated in part by fat cells.

Activity of Insulin/IGF-1 Signaling Pathways Reduces Life Span

The most clear-cut evidence that endocrine activity can bring about aging is that, in Caenorhabditis elegans, Drosophila, and mammals, life span is increased by inactivation of genes encoding components of the insulin/IGF-1 signaling pathway (see Warner Subfield History and "One for All"). This area has been reviewed recently (13, 14), and so we focus here on neuroendocrine aspects of insulin/IGF-1 signaling.

In mammals, effects of the insulin/IGF-1 signaling pathway clearly entail a neuroendocrine mechanism. As indicated above, disruption of neuroendocrine systems, including the GHRH receptor (12) and the GH receptor (15; and see Laron mice), increases murine life span. The effects of the neuroendocrine GH system on life span are most likely to be mediated by a reduction in IGF signaling, because genetic disruption of the mouse IGF-1 receptor also increases life span (16; and see Igf1r+/– mice). Insulin itself may also regulate life span, as ablation of the insulin receptor in mouse adipose tissue can increase life span (17; and see "Lasting Without Fasting"). It should be emphasized that secretion of both IGF-1 (via GH) and insulin (via the autonomic nervous system) is under strict neuroendocrine control, and so aging is controlled to an extent by neuroendocrine activity.

Considerable data support the idea that effects of the insulin/IGF-1 system on longevity also involve neuroendocrine activity in C. elegans, in many respects the model organism of choice for gerontological studies (18; and see Johnson Subfield History. Reestablishing expression of the insulin/IGF-1 receptor DAF-2 in C. elegans neurons restores wild-type longevity in worms lacking the receptor in the rest of their cells (19). Furthermore, the destruction of specific gustatory neurons in C. elegans increases life span, an effect mediated at least in part by the insulin/IGF-1 pathway (20; and see "Tasting Longevity"). Thus, insulin/IGF-1 signaling that is restricted to neurons is sufficient to drive the aging process. On the other hand, the daf-16 gene encodes a transcription factor that is required for insulin/IGF-1 signaling, and this appears to regulate life span not directly in neurons but through expression in fat cells in C. elegans (21; and see "Visceral Reaction"). Effects of the insulin/IGF-1 pathway on longevity therefore entail not only neuroendocrine effects but also events in other tissues, including tissues that produce fat. Interestingly, in a recent study (22; and see Antebi Perspective) the fly equivalent of the daf-16 gene was expressed in specific tissues, and as in C. elegans (21) the effect of this gene on life span was observed only when expressed in fat cells, in this case the fat body of the head. However, further data suggested that these effects were mediated at least in part by effects on neurons. Taken together with studies demonstrating an important role for insulin signaling in fat cells to regulate mammalian longevity (17), these data suggest that neuroendocrine communication between fat cells and neurons plays a key role in controlling the aging process. The nature of this communication remains to be determined, but hormonal links between adipose tissue and neuroendocrine systems are now well-established (involving effects of the adipose hormone leptin on hypothalamic neurons, for example, as indicated in Fig. 1). The identity of such links serving to mediate effects of insulin/IGF-1 signaling on longevity will no doubt be the subject of intense investigation.

Activity of the Reproductive System Decreases Life Span

Wild animals provide some striking examples of aging and death following neuroendocrine activity involving the reproductive system. Pacific salmon (genus Oncorhynchus), for example, are famous for their dramatic degeneration after spawning. Juveniles can survive for one or more years in the Pacific Ocean, but feeding ceases during migration up freshwater streams for spawning. Degenerative changes that are seen throughout somatic tissues include vascular endothelial proliferation leading to coronary vessel atheromas (thickening and degeneration of the inner layer of the artery), immunological impairments, and skeletal muscular atrophy. The neuroendocrine basis for these reproduction-associated degenerative changes is thought to involve a massive elevation of catabolic activity, correlated with elevated secretion of glucocorticoids such as cortisol, which is in turn dependent on reproductive hormones. Castration of juveniles prevents the elevation of cortisol concentrations--castrates continue to grow, with some surviving to double the natural life span (23). The adverse consequences of cortisol elevation to immune and vascular functions can be considered as trade-offs in the cost of reproduction, in which an elevated cortisol concentration enhances fitness through mobilization of metabolic reserves, but at the expense of acute impairments to somatic defense mechanisms and chronic preconditions for vascular pathology. Strikingly, the reproductive tissues of the migratory fish appear unscathed by these physiological extremes, despite exposure to corticosteroids at concentrations that would inhibit reproduction in most mammals.

Studies in C. elegans have provided the most compelling evidence that activity of the reproductive system limits life span (24-26; and see Arantes-Oliveira Science paper). In fact, removing the gonads of C. elegans increases life span by more than 60% (24), and when combined with inactivation of the insulin/IGF-1 signaling pathway by genetic means, can increase life span up to 6-fold (26; and see "Guinness-Bound"). This remarkable effect on life span appears to be a result not of sterility itself but of a reduction in some as-yet-undefined endocrine signal or signals (24).

Studies in female insects have elegantly demonstrated a direct relation between reproductive activity and a shortened life span, recently reviewed by Tatar (see Tatar Perspective). Sterilization by elevated temperature increases longevity of female Drosophila (27), and sterilization by radiation increases longevity of female flour beetles (28). As with C. elegans, the life-extending effects of these treatments are probably mediated by endocrine signals, because radiation increases the life span of fertile, but not ovaryless, Drosophila (29). These studies suggest that ovarian activity per se is associated with a cost to longevity.

The Neuroendocrine Stress Response System Can Reduce Life Span

The twin concepts that stress causes age-correlated deterioration and that age is associated with impaired response to stress have been discussed for decades (23, 30). Selye reported that in rats chronic psychological stress can lead to numerous pathologies, such as peptic ulcers and impaired immune responses (30). The key conclusion derived from these studies is that the stereotypic stress response itself, as opposed to the environmental factors, can lead to physiological impairments. Although recent studies clearly demonstrate that different painful or threatening stimuli produce quantitatively different responses, virtually all such stimuli cause activation of the sympathetic nervous system (especially an elevation of plasma catecholamines), otherwise known as the "fight or flight" response, and an increased secretion of glucocorticoids. For purposes of the current discussion, "stress" refers to stimuli that activate both the sympathetic nervous system and the glucocorticoid system, because raised activity of these two systems constitutes the most important element of the stress response.

The most compelling data supporting a link between stress and mortality in humans are reported in a growing literature examining mortality data in populations exposed to a well-defined common traumatic event. Probably the best example of this literature is a report by Leor et al. (31), which indicated that the number of sudden deaths from cardiac causes almost doubled the day after an earthquake. Remarkably similar results were obtained after other major earthquakes (32, 33) or following the death of a spouse (34). Based on their data, Leor and co-workers estimated that about 40% of sudden deaths in individuals with cardiovascular disease are likely to be triggered by stress-response mechanisms (it is generally assumed that stress-induced acute myocardial infarction is due to the stress-induced increase in sympathetic nervous stimulation of heart rate, which produces demands on the heart with which blood flow cannot keep up, precipitating cardiac arrhythmia, ischemia, and fatal infarction). As deaths caused by acute myocardial infarction (which equate roughly to the number of sudden deaths due to cardiovascular disease) account for about 10% of all deaths in the United States (National Center for Health Statistics, see "Deaths: Final Data for 2001"), this leads to the striking conclusion that about 5% of all deaths in the United States may be ascribed to acute effects of the neuroendocrine stress response on cardiac output. Thus, this single component of the neuroendocrine stress response may be responsible for about as many deaths as all accidents (including motor vehicle accidents), all cerebrovascular diseases (stroke), or all cancers of the reproductive tract (including breast and prostate cancer) combined (National Center for Health Statistics).

While it is clear that acute activation of a stress response can increase mortality, data supporting a long-term effect of stress on mortality are much less clear. Exposure to extremely high levels of stress appears to have deleterious effects on longevity in humans, although in such cases it is often difficult to distinguish between the effects of the stress and the effects of the stress response. For example, a remarkable study by Eitinger and Strom (35) studied the mortality patterns of Norwegian citizens who had been held as prisoners of war in Nazi concentration camps during World War II. In this study, the major effects of the stressful condition were on mortality within the first few years after release, largely from tuberculosis. Nevertheless, some long-term effects of the stress were indicated by the elevated death rates of these former prisoners during the 20 years following their release, which appeared to be about 40% higher than would be expected on the basis of comparison with former "ordinary prisoners" (who had not been held in concentration camps). Interestingly, concentration camp survivors were about twice as likely to die of cardiovascular disease as former ordinary prisoners, while the likelihood of dying from pneumonia was about the same (although it should be noted that these conclusions are based on necessarily small numbers of long-time survivors).


In contrast to earlier thinking, in which the failure of neuroendocrine systems was hypothesized to drive the aging process, the examples discussed above demonstrate that in fact the activity of neuroendocrine systems limits longevity. Indeed, of the genes whose inactivation has been shown to increase life span in mammals, neuroendocrine function may be decreased in almost all cases. The phenomenon of senescence as a consequence of neuroendocrine activity may have evolved by "antagonistic pleiotropy," in which selection for early reproductive success could permit postponed deleterious effects (see "Aging Research Grows Up").

This new perspective raises many new questions, two of which are particularly salient. First, although several lines of evidence suggest that caloric restriction (CR; see Masoro Subfield History) increases life span through neuroendocrine mechanisms, this conclusion has yet to be demonstrated definitively (36). Surprisingly, data suggest that the ability of CR to increase life span is independent of insulin/IGF-1 signaling (37, 38), and other manipulations that extend life span do not entail obvious neuroendocrine functions (39; and see Melov Perspective). Therefore, the extent to which neuroendocrine mechanisms underlying the aging process involve common pathways also involved in the regulation of life span by CR and other manipulations remains unclear. Second, although it may seem obvious that neuroendocrine systems function to increase fitness, this is clearly not the case under many laboratory conditions (because the inactivation of these systems increases life span and often increases total life-span fecundity as well). A key challenge is therefore to ascertain the precise environmental conditions under which these neuroendocrine systems do increase fitness. Further research would set the stage for designing mechanistic interventions to retard age-related morbidity and mortality by attenuating the activity of specific neuroendocrine pathways.

September 1, 2004
  1. C. V. Mobbs, in Handbook of the Biology of Aging (Academic Press, San Diego, 1996), pp. 234-283.
  2. X. Xu, W. E. Sonntag, Growth hormone and the biology of aging. In Functional Endocrinology of Aging, C. V. Mobbs, P. Hof, Eds. (Karger, Basel, 1998), pp. 67-88.
  3. G. G. Olsen, A. V. Everitt, Retardation of the ageing process in collagen fibres from the tail tendon of the old hypophysectomized rat. Nature 206, 307-08(1965).[Medline]
  4. F. Verzar, H. Spichtin, The role of the pituitary in the aging of collagen. Gerontologia 12, 48-56 (1966).[Medline]
  5. A. V. Everitt, The hypothalamic-pituitary control of ageing and age-related pathology. Exp. Gerontol. 8, 265-277 (1973).[CrossRef][Medline]
  6. J. R. Wyndham, A. V. Everitt, A. Eyland, J. Major, Inhibitory effect of hypophysectomy and food restriction on glomerular basement membrane thickening, proteinuria, and renal enlargement in aging male wistar rats. Arch. Gerontol. Geriatr. 6, 323-337 (1987).[CrossRef][Medline]
  7. A. V. Everitt, C. D. Shorey, M. A. Ficarra, Skeletal muscle aging in the hind limb of the old male wistar rat: Inhibitory effect of hypophysectomy and food restriction. Arch. Gerontol. Geriatr. 4, 101-115 (1985).[CrossRef][Medline]
  8. C. D. Shorey, L. A. Manning, A. V. Everitt, Morphometrical analysis of skeletal muscle fibre ageing and the effect of hypophysectomy and food restriction in the rat. Gerontology 34, 97-109 (1988).[Medline]
  9. E. C. Jones, P. L. Krohn, Influence of the anterior pituitary on the ageing process in the ovary. Nature 183, 1155-1158 (1959).[CrossRef][Medline]
  10. A. V. Everitt, N. J. Seedsman, F. Jones, The effects of hypophysectomy and continuous food restriction, begun at ages 70 and 400 days, on collagen aging, proteinuria, incidence of pathology, and longevity in the male rat. Mech. Ageing Dev. 12, 161-172 (1980).[CrossRef][Medline]
  11. H. M. Brown-Borg, K. E. Borg, C. J. Meliska, A. Bartke, Dwarf mice and the ageing process. Nature 384, 33 (1996).[CrossRef][Medline]
  12. K. Flurkey, J. Papaconstantinou, R. A. Miller, D. E. Harrison, 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 (2001).[Abstract/Free Full Text]
  13. L. Guarente, C. Kenyon, Genetic pathways that regulate ageing in model organisms. Nature 408, 255-262 (2000).[CrossRef][Medline]
  14. M. Tatar, A. Bartke, A. Antebi, The endocrine regulation of aging by insulin-like signals. Science 299, 1346-1351 (2003).[Abstract/Free Full Text]
  15. K. T. Coschigano, D. Clemmons, L. L. Bellush, J. J. Kopchick, Assessment of growth parameters and life span of ghr/bp gene-disrupted mice. Endocrinology 141, 2608-2613 (2000).[CrossRef][Medline]
  16. M. Holzenberger, J. Dupont, B. Ducos, P. Leneuve, A. Geloen, P. C. Even, P. Cervera, Y. Le Bouc, Igf-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182-187 (2003).[CrossRef][Medline]
  17. M. Bluher, B. B. Kahn, C. R. Kahn, Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572-574 (2003).[Abstract/Free Full Text]
  18. T. E. Johnson, Advantages and disadvantages of Caenorhabditis elegans for aging research. Exp. Gerontol. 38, 1329-332 (2003).[CrossRef][Medline]
  19. C. A. Wolkow, K. D. Kimura, M. S. Lee, G. Ruvkun, Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science 290, 147-150 (2000).[Abstract/Free Full Text]
  20. J. Alcedo, C. Kenyon, Regulation of C. elegans longevity by specific gustatory and olfactory neurons. Neuron 41, 45-55 (2004).[CrossRef][Medline]
  21. N. Libina, J. R. Berman, C. Kenyon, Tissue-specific activities of C. elegans daf-16 in the regulation of lifespan. Cell 115, 489-502 (2003).[CrossRef][Medline]
  22. D. S. Hwangbo, B. Gersham, M. P. Tu, M. Palmer, M. Tatar, Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429, 562-566 (2004).[CrossRef][Medline]
  23. O. H. Robertson, B. C. Wexler, B. F. Miller, Degenerative changes in the cardiovascular system of the spawning pacific salmon (Oncorhynchus tshawytscha). Circ. Res. 9, 826-834 (1961).[Abstract/Free Full Text]
  24. H. Hsin, C. Kenyon, Signals from the reproductive system regulate the lifespan of C. elegans. Nature 399, 362-366 (1999).[CrossRef][Medline]
  25. N. Arantes-Oliveira, J. Apfeld, A. Dillin, C. Kenyon, Regulation of life-span by germ-line stem cells in Caenorhabditis elegans. Science 295, 502-505 (2002).[Abstract/Free Full Text]
  26. N. Arantes-Oliveira, J. R. Berman, C. Kenyon, Healthy animals with extreme longevity. Science 302, 611 (2003).[Free Full Text]
  27. J. Maynard-Smith, The effects of temperature and of egg laying on the longevity of Drosophila subobscura. J. Exp. Biol. 35, 832-842 (1958). [Abstract]
  28. J. M. Cork, Gamma-radiation and longevity of the flour beetle. Radiat. Res. 7, 551-557 (1957).[Medline]
  29. T. Chapman, J. Hutchings, L. Partridge, No reduction in the cost of mating for Drosophila melanogaster females mating with spermless males. Proc. R. Soc. Lond. B Biol. Sci. 253, 211-217 (1993).[Medline]
  30. H. Selye, Forty years of stress research: Principal remaining problems and misconceptions. Can. Med. Assoc. J. 115, 53-66 (1976).[Abstract]
  31. J. Leor, W. K. Poole, R. A. Kloner, Sudden cardiac death triggered by an earthquake. N. Engl. J. Med. 334, 413-419 (1996).[CrossRef][Medline]
  32. D. Trichopoulos, K. Katsouyanni, X. Zavitsanos, A. Tzonou, P. Dalla-Vorgia, Psychological stress and fatal heart attack: The Athens (1981) earthquake natural experiment. Lancet 1, 441-444 (1983).[CrossRef][Medline]
  33. K. Katsouyanni, M. Kogevinas, D. Trichopoulos, Earthquake-related stress and cardiac mortality. Int. J. Epidemiol. 15, 326-330 (1986).[Abstract/Free Full Text]
  34. P. J. Clayton, Mortality and morbidity in the first year of widowhood. Arch. Gen. Psychiatry 30, 747-750 (1974).[CrossRef][Medline]
  35. L. Etinger, A. Strom, Mortality and Morbidity After Excessive Stress (Humanities Press, New York, 1973).
  36. C. V. Mobbs, G. A . Bray, R. L. Atkinson, A. Bartke, C. E. Finch, E. Maratos-Flier, J. N. Crawley, J. F. Nelson, Neuroendocrine and pharmacological manipulations to assess how caloric restriction increases life span. J. Gerontol. A Biol. Sci. Med. Sci. 56, 34-44 (2001).[Abstract/Free Full Text]
  37. A. Bartke, J. C. Wright, J. A. Mattison, D. K. Ingram, R. A. Miller, G. S. Roth, Extending the lifespan of long-lived mice. Nature 414, 412 (2001).[CrossRef][Medline]
  38. K. Houthoofd, B. P. Braeckman, T. E. Johnson, J. R. Vanfleteren, Life extension via dietary restriction is independent of the ins/igf-1 signalling pathway in Caenorhabditis elegans. Exp. Gerontol. 38, 947-954 (2003).[CrossRef][Medline]
  39. S. S. Lee, R. Y. Lee, A. G. Fraser, R. S. Kamath, J. Ahringer, G. Ruvkun, A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nature Genet. 33, 40-48 (2003).[CrossRef][Medline]
  40. This paper is based on an original draft written with Dr. Caleb Finch, whose contributions are gratefully acknowledged. However, any errors in fact or perspective are entirely the author's own. Supported in part by NIA (AG19934-01).
Citation: C. V. Mobbs, Not Wisely but Too Well: Aging as a Cost of Neuroendocrine Activity. Sci. Aging Knowl. Environ. 2004 (35), pe33 (2004).

Science of Aging Knowledge Environment. ISSN 1539-6150