Journals of Gerontology Series A: Biological Sciences and Medical Sciences Large Type Edition
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Euser, S. M.
Right arrow Articles by Westendorp, R. G. J.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Euser, S. M.
Right arrow Articles by Westendorp, R. G. J.
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 63:907-910 (2008)
© 2008 The Gerontological Society of America

Insulin/Insulin-Like Growth Factor-1 Signaling and Cognitive Function in Humans

Sjoerd M. Euser, Diana van Heemst, Peter van Vliet, Monique M. B. Breteler and Rudi G. J. Westendorp

1 Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
2 Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.

Address correspondence to Sjoerd M. Euser, MSc, Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, the Netherlands (E-mail: s.euser{at}lumc.nl) or Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands (E-mail: s.euser{at}erasmusmc.nl)


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
An accumulating body of evidence suggests the involvement of an evolutionary conserved insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) pathway in the regulation of the life and health span in nematodes, flies, rodents, and humans. We studied the association between insulin/IGF-1 signaling and cognitive function among 1015 participants, 85 years old or older, of the population-based Leiden 85-Plus Study. A composite IIS6 score, based on expected effects (increased or decreased signaling) of selected variants in the IIS pathway, was calculated to estimate IIS pathway activity. Cognitive function was assessed at baseline and annually during a 5-year follow-up, using the Mini-Mental State Examination (MMSE). In women, but not in men, lower IIS6 scores (indicating decreased signaling) were associated with a lower risk of cognitive impairment (MMSE score ≤ 18) (p trend =.010). The IIS6 score was not associated with change in cognitive function. In addition to old age survival, genetically reduced IIS seems to be beneficial for cognitive function in women.

Key Words: Insulin/IGF-1 signaling • Cognitive function • Cohort study • Human

THE involvement of the evolutionary conserved insulin (INS)/insulin-like growth factor-1 (IGF-1) signaling (IIS) pathway in the hormonal regulation of aging has been shown in a number of model organisms like nematodes, flies, and rodents (1–8). Genetic variation that causes a reduced IIS activation was associated with an increased life span in these organisms, with a stronger effect seen in the female sex (6,9–11). In accordance with these data on model organisms, we previously showed an association between a genetically reduced IIS pathway and better survival in elderly women (12).

Moreover, in model organisms, the IIS pathway has not only been implicated in the determination of life span but also in that of health span. At old age, there is a high prevalence of cognitive impairment, which for many is one of the most frightening prospects of old age. An accumulating body of evidence suggests the involvement of INS and IGF-1 in the development of cognitive impairment (13–15). Suggested biological mechanisms that underlie this relationship are inhibition of the amyloid β breakdown (through the INS-degrading enzyme) and the involvement of INS and IGF-1 in {tau} phosphorylation (14,16,17). In humans, it is yet to be elucidated how the evolutionary conserved IIS pathway, which has been shown to be associated with better survival in old age, is related to cognitive function and decline.

Therefore, we studied the relationship between genetic variation in IIS pathway activation and cognitive function and decline in a prospective, population-based study among 1015 participants of the Leiden 85-Plus Study.


   METHODS
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Population
The Leiden 85-Plus Study is a prospective, population-based cohort study that consists of two cohorts of inhabitants of Leiden, the Netherlands (18,19). For cohort '87, 977 inhabitants of Leiden, 85 years old or older, were enrolled between 1987 and 1989, and cognitive function was assessed at baseline. For cohort '97, 599 inhabitants of Leiden, 85 years old, were enrolled between 1997 and 1999. Cognitive function was assessed at baseline and annually during home visits, from age 85 until age 90 years. Of the 1576 participants in the two cohorts of the Leiden 85-Plus Study, DNA was available for 1245 participants, and IIS scores could be calculated for 1037 participants (12). Twenty-two participants did not have cognitive data available at baseline, resulting in a study sample of 1015 participants.

IIS Score
To determine the genetic variation that influences IIS, we selected six polymorphisms in five genes from the IIS pathway (growth hormone–releasing hormone receptor [GHRHR], growth hormone 1 [GH1], IGF-1, INS, and INS receptor substrate-1 [IRS1]) based on previous reports of their effects on gene expression or protein function. As the effect sizes of the six selected IIS polymorphisms were unknown, these were assumed to be equal, and a simple additive model (hereafter referred to as IIS6 score) was used to test for combined effects of the selected polymorphisms. Per individual, we calculated a composite IIS6 score by assessing a value of –1 for carriership of each variant predicted to cause reduced IIS activity (GHRHR rs4988496, GH1 rs2665802, IGF-1 CA repeat, INS variable number tandem repeats (VNTR), IRS1 rs1801278), and a value of +1 for carriership of the variant predicted to cause increased IIS activity (IGF1 CT repeat). In total, the IIS6 score could be calculated for 1037 of the 1245 participants for whom DNA was available. Because of the limited number of participants (n = 3) with an IIS6 score of –5, we included these participants in the IIS6 score –4 category. Likewise, the participants in the IIS6 score +1 category (n = 6) were included in the IIS6 score 0 category. A more detailed description of the selected polymorphisms and assessment of the IIS6 score have been published elsewhere (12).

Cognitive Function
Cognitive function was assessed with the Mini-Mental State Examination (MMSE) (20), and was available for 1015 participants of both cohorts at baseline. The MMSE is a measure of global cognitive function and ranges from 0 to 30 points, with lower scores indicating worse cognitive function. Although the MMSE is a widely used test that was developed as a screening instrument for dementia and is a reliable measure of global cognitive function, it might lack reliability and validity in persons with severe cognitive impairment (21). Therefore, we dichotomized the cognitive test scores and defined cognitive impairment as an MMSE-score ≤ 18 points. Additionally, 455 of the 511 participants of cohort '97 underwent at least one measurement of the MMSE during follow-up, resulting in a study sample of 455 participants available for the longitudinal analyses. Annual change in cognitive function was assessed by comparing test scores at baseline with those at the last available follow-up visit. Annual change in cognitive function was calculated as the difference between test score at baseline and test score at the last available year of follow-up, divided by the length of follow-up (1–5 years).

Statistical Analyses
The relationship between the IIS6 score and the risk of cognitive impairment was assessed with logistic regression models.

The relationship between the IIS6 score and the annual change in cognitive function during follow-up was assessed with analyses of covariance, with the annual change in cognitive function as the dependent variable, and the IIS6 score as the grouping variable. To assess the association between the 1-unit increase in IIS6 score and the annual change in cognitive function, we used linear regression models with the annual change in MMSE score as the dependent variable and the IIS6 score as the independent variable.

All analyses were adjusted for age and carried out using the SPSS statistical package (release 12.0.1; SPSS, Inc., Chicago, IL).


   RESULTS
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Table 1 shows the baseline characteristics of the study participants. The mean age of the 1015 participants from the combined cohorts of the Leiden 85-Plus Study was 87.4 years, and 68% were women. Mean MMSE score at baseline was 23.9 points and ranged from 0 to 30 points.


View this table:
[in this window]
[in a new window]

  		Table 1. Baseline Characteristics.

 
Table 2 shows the sex-specific relationship between the composite IIS6 score and the risk of cognitive impairment, adjusted for age. A higher IIS6 score was associated with a higher risk of cognitive impairment, but only for women (odds ratio [95% confidence interval] per 1-unit increase in IIS6 score was 1.28 [1.06–1.53], p =.010). In men, a higher IIS6 score was, if anything, associated with a lower risk of cognitive impairment (odds ratio [95% confidence interval] per 1-unit increase in IIS6 score was 0.85 [0.60–1.19], p =.329).


View this table:
[in this window]
[in a new window]

  		Table 2. Association Between Insulin/IGF-1 Signaling Score and the Risk of Cognitive Impairment in the Leiden 85-Plus Study.

 
The longitudinal analyses, which were performed of 455 participants of cohort '97 only, showed no clear relationship between the IIS6 score and the annual change in cognitive function during follow-up. In both women (annual change in MMSE score [standard error {SE}]) per 1-unit increase in IIS6 score was –0.06 [0.12] points, p =.612) and men (annual change in MMSE-score [SE] per 1-unit increase in IIS6 score was –0.16 [0.15] points, p =.311) a higher IIS6 score was not associated with an accelerated or decelerated rate of decline in cognitive function during follow-up.


   DISCUSSION
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Our study showed that, in humans, a genetically reduced IIS pathway was associated with a lower risk of cognitive impairment in women, but not in men. There was no association between the IIS pathway and a change in cognitive function over time.

Together with our previous finding that showed an association between a genetically reduced IIS pathway with improved old age survival in women (12), our current findings are in accordance with the available data from model organisms that showed favorable effects of genetically induced lower IIS activity on both life span and health span. In model organisms, such as Caenorhabditis elegans, down-regulation of the IIS pathway occurs in response to adverse environmental conditions, such as food shortage. Its main function is to coordinately adapt various aspects of the worm's physiology, so that priorities are changed from growth and reproduction to mere survival until conditions become more favorable. In C. elegans, environmentally, as well as genetically induced down-regulation of the IIS pathway can dramatically increase life span, with concurrent maintenance of functional abilities (22). Furthermore, it was shown that the mutations in the IIS pathway are associated with associative learning behavior in C. elegans (23).

At first glance, the beneficial effects of genetically induced down-regulation of the IIS pathway seem to conflict with the available data on the association of IGF-1 serum levels with the human health span. In humans, the activity of the hypothalamic–GH–IGF-1 axis declines with age, and several aspects of functional decline, including cognitive decline, have been attributed to the somatopause. In several studies, higher levels of total circulating IGF-1 were associated with better cognitive function and less cognitive decline in elderly persons (24,25), although in at least one study, free IGF-I levels were not associated with cognitive decline (25). The a priori prediction based on the genetic data from long-lived worms would have predicted an association between low serum IGF-1 levels (instead of high levels) and improved survival and better maintenance of functional abilities (22). Recently, a similar paradox was observed in mice: Decreased IGF-1 levels are not only a key feature of the serum profile of long-lived mice, such as calorically restricted wild-type mice, but also of mice that are short-lived due to mutations in DNA repair (26,27). The picture that now emerges is that down-regulation of IIS is an ancient survival response that can occur both in response to sudden external stresses (such as food shortage) as well as in response to chronic internal stresses (such as the accumulation of damage with aging) (28). Likewise, in humans, the decline in GH/IGF-1 levels with age may be an adaptive response aimed to prolong survival. According to this hypothesis, higher serum IGF-1 levels in old age might be indicative of a lower degree of (age-associated) accumulated damage.

The observed sex-specific involvement of IIS pathway activity in the development of cognitive impairment that is presented here is supported by previous findings. In the first discovered long-lived C. elegans mutant that mapped to the IIS pathway, both male and hermaphrodite worms were shown to be affected by age (1). Moreover, in female but not in male rats, heightened cognition, in addition to increased motor activity and reproductive shutdown, was observed as an important aspect of the survival response to caloric restriction (29). Improved learning and memory may play important roles in the success of seeking food elsewhere, which is especially important for the female sex, as females must obtain sufficient energy to support the survival and development of their offspring as well as themselves. The possible, not mutually exclusive, mechanisms by which reduced IIS pathway activity may contribute to heightened cognition in elderly women, include increased stress resistance and reduced amyloid β-induced autophagosome accumulation. Recent data obtained in a C. elegans model suggest that reduced IIS activity promotes the maturation of autophagosomes into degradative autolysosomes, whereas amyloid β impairs this process (30). Another study showed the involvement of IIS pathway mediation in the aggregation-mediated amyloid-β toxicity in C. elegans (31).

The observed association between a lower IIS6 score and better cognitive function was not seen in the longitudinal analyses. A lower IIS6 score was not associated with an accelerated or decelerated rate of decline in cognitive function during follow-up. A possible explanation could be that there were only longitudinal data on cognitive function available for the participants of cohort '97, which reduced our sample size and concurrently the statistical power of our analyses. Furthermore, it has been suggested that in situations with substantial dropout during follow-up, cross-sectional analyses may provide the better estimates (32,33). Therefore, cross-sectional estimates might have been the preferred choice here to study the relationship between IIS and cognition as we were testing the consequence of genetic variants that have accumulated over a lifetime. Alternatively, genetically determined lifelong lower IIS activity may mainly have an effect on the onset of cognitive decline (postponing it to a later age) and not on the rate of the decline.

Conclusion
We showed that genetically reduced IIS seems to be beneficial for cognitive function in women but not in men. These results are in line with our previous findings that showed associations between reduced IIS signaling and increased longevity in women, and further indicates the involvement of the IIS pathway in the regulation of health span.


   Acknowledgments
Top
 Abstract
 Methods
 Results
 Discussion
 References
 
This study was supported by The Netherlands Organization for Scientific Research (NWO), Research Institute for Diseases in the Elderly (RIDE) grants 948-00-009 and 948-00-921, and by the International Foundation Alzheimer's Research.


   Footnotes
Top
 Abstract
 Methods
 Results
 Discussion
 References
 
Decision Editor: Huber R. Warner, PhD

Received March 6, 2008

Accepted June 22, 2008


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Johnson TE. Increased life-span of age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging. Science. 1990;249:908-912.[Abstract/Free Full Text]
  2. Kenyon C. A conserved regulatory system for aging. Cell. 2001;105:165-168.[Medline]
  3. Kinney BA, Coschigano KT, Kopchick JJ, Steger RW, Bartke A. Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice. Physiol Behav. 2001;72:653-660.[Medline]
  4. Kinney BA, Meliska CJ, Steger RW, Bartke A. Evidence that Ames dwarf mice age differently from their normal siblings in behavioural and learning and memory parameters. Horm Behav. 2001;39:277-284.[Medline]
  5. Blüher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003;299:572-574.[Abstract/Free Full Text]
  6. Holzenberger M, Dupont J, Ducos B, et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature. 2003;421:182-187.[Medline]
  7. Tatar M, Bartke A, Antebi A. The endocrine regulation of aging by insulin-like signals. Science. 2003;299:1346-1351.[Abstract/Free Full Text]
  8. Piper MDW, Selman C, McElwee JJ, Partridge L. Separating cause from effect: how does insulin/IGF signaling control lifespan in worms, flies and mice? J Intern Med. 2008;263:179-191.[Medline]
  9. Migliaccio E, Giorgio M, Mele S, et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature. 1999;402:309-313.[Medline]
  10. Clancy DJ, Gems D, Harshman LG, et al. Extension of life-span by loss of CHICO, a drosophila insulin receptor substrate protein. Science. 2001;292:104-106.[Abstract/Free Full Text]
  11. Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science. 2000;292:107-110.
  12. Van Heemst D, Beekman M, Mooijaart SP, et al. Reduced insulin/IGF-1 signalling and human longevity. Aging Cell. 2005;4:79-85.[Medline]
  13. Gasparini L, Xu H. Potential roles of insulin and IGF-1 in Alzheimer's disease. Trends Neurosci. 2003;26:404-406.[Medline]
  14. Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I. Serum insulin-like growth factor 1 regulates brain amyloid-β levels. Nat Med. 2002;8:1390-1397.[Medline]
  15. Selkoe DJ. Clearing the brain's amyloid cobwebs. Neuron. 2001;32:177-180.[Medline]
  16. Schubert M, Brazil DP, Burks DJ, et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci. 2003;23:7084-7092.[Abstract/Free Full Text]
  17. Hong M, Lee VMY. Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem. 1997;272:19547-19553.[Abstract/Free Full Text]
  18. Bootsma-van der Wiel A, van Exel E, de Craen AJM, et al. A high response is not essential to prevent selection bias: results from the Leiden 85-Plus Study. J Clin Epidemiol. 2002;55:1119-1125.[Medline]
  19. Slagboom PE, Heijmans BT, Beekman M, Westendorp RGJ, Meulenbelt I. Genetics of human aging. The search for genes contributing to human longevity and diseases of the old. Ann N Y Acad Sci. 2000;908:50-63.[Medline]
  20. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198.[Medline]
  21. Tombaugh TN, McIntyre NJ. The Mini-Mental State Examination: a comprehensive review. J Am Geriatr Soc. 1992;40:922-935.[Medline]
  22. Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature. 2000;408:255-262.[Medline]
  23. Murakami H, Bessinger K, Hellmann J, Murakami S. Aging-dependent and -independent modulation of associative learning behavior by insulin/insulin-like growth factor-1 signal in Caenorhabditis elegans. J Neurosci. 2005;25:10894-10904.[Abstract/Free Full Text]
  24. Paolisso G, Ammendola S, Del Bueno A, et al. Serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in healthy centenarians: relationship with plasma leptin and lipid concentrations, insulin action, and cognitive function. J Clin Endocrinol Metab. 1997;82:2204-2209.[Abstract/Free Full Text]
  25. Kalmijn S, Janssen JA, Pols HA, Lamberts SW, Breteler MM. A prospective study on circulating insulin-like growth factor I (IGF-I), IGF-binding proteins, and cognitive function in the elderly. J Clin Endocrinol Metab. 2000;85:4551-4555.[Abstract/Free Full Text]
  26. Niederhofer LJ, Garinis GA, Raams A, et al. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature. 2006;444:1038-1043.[Medline]
  27. Kirkwood T. Too fast by mistake. Nature. 2006;444:1015-1017.[Medline]
  28. Schumacher B, Garinis GA, Hoeijmakers JHJ. Age to survive: DNA damage and aging. Trends Genet. 2008;24:77-85.[Medline]
  29. Martin B, Pearson M, Kebejian L, et al. Sex-dependent metabolic, neuroendocrine, and cognitive responses to dietary energy restriction and excess. Endocrinology. 2007;148:4318-4333.
  30. Florez-McClure ML, Hohsfield LA, Fonte G, Bealor MT, Link CD. Decreased insulin-receptor signaling promotes the autophagic degradation of β-amyloid peptide in C. elegans. Autophagy. 2007;3:569-580.[Medline]
  31. Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A. Opposing activities protect against age-onset proteotoxicity. Science. 2006;313:1604-1610.[Abstract/Free Full Text]
  32. Euser SM, Schram MT, Hofman A, Westendorp RGJ, Breteler MMB. Measuring cognitive function with age: the influence of selection by health and survival. Epidemiology. 2008;19:440-447.[Medline]
  33. Hernán MA, Alonso A, Logroscino G. Cigarette smoking and dementia; potential selection bias in the elderly. Epidemiology. 2008;19:448-450.[Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Euser, S. M.
Right arrow Articles by Westendorp, R. G. J.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Euser, S. M.
Right arrow Articles by Westendorp, R. G. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
All GSA journals The Gerontologist
Journals of Gerontology Series B: Psychological Sciences and Social Sciences