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Peptides, memory, food intake and aging J.E. Morley, J.F. Flood, H.M. Perry III, and V.B. Kumar Geriatric Research, Education and Clinical Center, St. Louis VA Medical Center, and Division of Geriatrics, Saint Louis University School of Medicine, St. Louis, MO, U.S.A.

Aging is associated with physiological changes in memory and food intake. While the role of neurotransmitters in the physiology of these processes has not still been clearly delineated, over the last decade numerous studies have provided intriguing clues to the role of peptides in the pathophysiology of a number of these age related changes. AMYLOID-BETA PROTEIN, MEMORY AND THE SAMP8 MOUSE The SAMP8 mouse is an excellent model of early onset of deficits in acquisition and retention (1). Pharmacological studies have demonstrated that the SAMP8 mouse has a deficit in the functioning of the septo-hippocampal pathway. In particular, these mice have a clear-cut deficit in cholinergic function in the hippocampus (2). We have demonstrated that the SAMP8 mouse overproduces amyloid-beta-protein precursor protein (APP) and its mRNA in the hippocampus (3). Amyloid-beta-protein is amnestic when administered intracerebro-ventricularly (ICV) (4), and we have developed a number of peptide antagonists to amyloid-beta-protein, e.g. DFFVG, that will reverse the amnestic effect of amyloid-beta protein (5). To test the functional significance of the overproduction of amyloid-beta-protein in the SAMP8 mice, we administered antibody to this peptide ICV to the mice and measured its effects on acquisition and retention. Antibody to amyloid-betaprotein reversed the deficits in acquisition and retention in the SAMP8 mouse (3). In addition, an antisense protein raised to the amyloid-beta-protein region reversed the acquisition deficit seen in the SAMP8 mouse while reducing APP production but not altering mRNA levels. In SAMP8 mice the acquisition and retention deficits occur at 8 to 12 months of age. At this time period no amyloid plaques are present in the brain. However, by 16 months of age, amyloid plaques are clearly present in the hippocampus of the SAMP8

mice. This finding suggests that amyloid plaques are an epiphenomenon of APP overproduction and unassociated with the memory deficits. We have studied the role of androgenic hormones in the development of the memory deficits in male SAMP8 mice (6). These mice have low testosterone levels by 12 months of age compared to the control strain (R1) of mice. The retention deficit is reversed by testosterone administration. Testosterone administration decreased APP levels in the hippocampus and the amygdala. These studies suggest that SAMP8 mice are an excellent spontaneous animal model for Alzheimer’s disease. Further, these findings suggest a crucial role for amyloid-beta-protein in the pathogenesis of the cognitive dysfunction in Alzheimer’s disease. Our studies also suggest that Alzheimer’s disease is an exaggeration of the normal aging process and occurs on a continuum with it. ANOREXIA OF AGING With aging there is a decline in food intake (7). This physiological decrease in food intake has been termed the anorexia of aging (8). Our studies in humans have suggested that this anorexia is partially related to alterations in gastric emptying rate, which leads to early satiation in healthy older persons (9). In older persons the stomach appears to play a more important role in modulating satiation and satiety than do nutrients in the small intestine. In animal studies we have demonstrated that the anorexia of aging is, in part, due to a decrease in the opioid (dynorphin) food drive with aging (10). In addition, there is evidence that the early satiation may be due in part to an increased satiating effect of cholecystokinin (CCK) (11). There is some evidence that with aging, CCK levels may increase in humans. Amylin is another peripheral peptide that may play a role in the anorexia of aging (12, 13). Nitric oxide has been dem-

Correspondence: John E. Morley, MB, Bch, Saint Louis University School of Medicine, 1402 S. Grand Blvd., Rm M238, St. Louis, MO 63104, U.S.A.

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onstrated to play an important role in modulating food intake. Nitric oxide produces its effects on food intake both by effects within the hypothalamus and effects on the fundus of the stomach. A decrease in fundal compliance plays a role in the early satiation seen in older persons. Alterations in nitric oxide synthase may play a role in this aspect of the anorexia of aging (14). Leptin is a peptide produced by adipose cells. With aging, in women there is a decline in leptin levels (15). Women have higher leptin levels than men. In males leptin levels increase with age. This increase in leptin is associated with the age-associated decline in testosterone levels (16). Testosterone administration decreased leptin levels in older males (17). Leptin may play a role in the anorexia of aging in older males. Overall these studies suggest that the pathophysiology of the anorexia of aging is associated with changes in multiple peptides. REFERENCES 1. Flood J.F., Morley J.E.: Age related impairment of aversive and appetitive learning in the SAMP8 mouse strain. A mode of dementia of early onset. J. Gerontol. 47: B52-B59, 1992. 2. Flood J.F., Morley J.E., LaReginna M.: Age-related changes in the pharmacological improvement of retention in senescence accelerated mouse. Neurobiol. Aging 14: 159-166, 1993. 3. Flood J.E., Morley J.E.: Learning and memory in the SAMP8 mouse. Neurosci. Biobehav. Rev. In press, 1997. 4. Flood J.F., Morley J.E., Roberts E.: Amnestic effects in mice of four synthetic peptide homologous to amyloid ` protein from Alzheimer disease. Proc. Natl. Acad. Sci. USA 88: 3363-3366, 1991. 5. Flood J.F., Roberts E., Sherman M.A., Kaplan B.E., Morley J.E.: Topography of a binding site for small amnestic peptides deduced from structure-activity studies. Relation to amnestic effect of amyloid `-protein. Proc. Natl. Acad. Sci.

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USA 91: 380-384, 1994. 6. Flood J.F., Farr S.A., Kaiser F.E., LaReginna M., Morley J.E.: Age-related decrease of plasma testosterone in SAMP8 mice: replacement improves age-related impairment of learning and memory. Physiol. Behav. 57: 669-673, 1995. 7. Morley J.E.: Anorexia in older persons: Epidemiology and optimal treatment. Drugs Aging 8: 134-155, 1996. 8. Morley J.E., Silver A.J.: Anorexia in the elderly. Neurobiol. Aging 9: 9-16, 1988. 9. Clarkston W.K., Pantano M.M., Morley J.E., Horowitz M., Littlefield J.M., Barton F.R.: Evidence for the anorexia of aging: Gastrointestinal transit and hunger in healthy elder vs. young adults. Am. J. Physiol. R243-248, 1997. 10. Gosnell B.A., Levine A.S., Morley J.E.: The effects of aging on opioid modulation of feeding in rats. Life Sci. 32: 27932799, 1983. 11. Silver A.J., Flood J.F., Morley J.E.: Effect of gastrointestinal peptides on ingestion in young and old mice. Peptides 9: 221-226, 1988. 12. Morley J.E., Flood J.F., Farr S.A., Perry H.M. III, Kaiser F.E., Morley P.M.K.: Effects of amylin on appetite regulation and memory. Can. J. Pharmacol. Physiol. 73: 1042-1046, 1995. 13. Edwards B.J., Perry H.M. III, Kaiser F.E., Morley J.E., Kraenzle D.M., Kreuter D.K., Stevenson R.W.: Age related changes in amylin secretion. Mech. Aging Develop. 86: 39-51, 1996. 14. Morley J.E., Kumar V.B., Mattammal M.B., Farr S.A., Morley P.M.K., Flood J.F.: Inhibition of feeding by L-NAME: Effects of aging. Eur. J. Pharmacol. 311: 15-29, 1996. 15. Perry H.M. III, Morley J.E., Horowitz M., Kaiser F.E., Miller D.K., Wittert G.: Body composition and age in African American and Caucasian women: relationship to plasma leptin levels and gonadal steroids. Metabolism, 1997, (in press.). 16. Morley J.E., Perry H.M. III, Kaiser F.E., Patrick P., Morley P.M.K., Stauber P.M., Baumgarter R., Vellas B., Garry P.: Longitudinal changes in testosterone, luteinizing hormone and follicle stimulating hormone in healthy older males. Metabolism 46: 410-413, 1996. 17. Sih R., Morley J.E., Kaiser F.E., Perry H.M. III: Testosterone replacement in older hypogonadal men: a 12 month randomized controlled trial. J. Clin. Endocrinol. Metab., 1997, (in press.).