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Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
Immunological markers of healthy/unhealthy ageing
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Immunological markers of healthy/unhealthy ageing

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  • 1. <ul><li>Hypothesis: </li></ul><ul><li>chronic </li></ul><ul><li>antigenic and inflammatory burden plays a pivotal role for human frailty and survival </li></ul>
  • 2. <ul><li>old people have to cope with a lifelong antigenic burden encompassing several decades of evolutionary unpredicted antigenic exposure </li></ul>
  • 3. INFLAMM-AGING Remodelling / Stress response Inflammatory response Optimal remodeling (hormesis) Low proinflammatory status High efficiency of stress response Inadequate remodeling High proinflammatory status Low efficiency of stress response Effects of stress AGE
  • 4. INFLAMM-AGING <ul><li>IL-6 </li></ul>
  • 5. 30 60 90 C - males have higher serum IL-6 in respect to age-matched C+ males and C+/C- females C- Males C- Females C+ Females C+ Males Genotype-sex interaction Age Serum IL-6
  • 6. &nbsp;
  • 7. <ul><li>IL-10 </li></ul>
  • 8. Inflamm-aging <ul><li>IL-10 </li></ul><ul><li>IL-10 is a major immunoregulatory cytokine which inhibits activation and effector function of T cells, monocytes and macrophages, and its principal routine function appears to limit and ultimately terminate inflammatory responses </li></ul>
  • 9. MALES Il - 10 &amp;quot;Functional Genotype&amp;quot; Il - 10 high production Il - 10 Low production Controls (89) % 27 73 N 24 65 Centenarians (65) % 44,6 55,4 N 29 36 Pearson Chi - square test: 5.184; df:1; p:0.026
  • 10. <ul><li>IL-6 and IGF1 </li></ul>
  • 11. INS/IGF1 R LONGEVITY DEVELOPMENT GLUCOSE METABOLISM NEMATODE FLY MOUSE INR  INR Chico IRS1-2 Dp110/p60 p85/p110  ? Forkhead transcription factor Insulin/IGF-1 Ligand DAF-2 ? AGE 1 DAF-16 Ligand GH GHR (-/-) INSULIN/IGF-1 SIGNALING PATHWAY: HUMAN HOMOLOGIES WITH NEMATODE, FLIES AND MICE HUMANS Insulin/IGF-1 p85/p110  IRS1 HNF3/Forkhead
  • 12. Am. J. Physiol. Endocrinol. Metab. 284: E481-E487, 2003
  • 13. &nbsp;
  • 14. Table 2. Correlations between IL-6, IL-6 receptor and IGF-1 and anthropometric and physical performance parameters (n=526) IL-6* p IL-6 receptor p IGF-1 p Age 0.36 &lt;.001 0.16 &lt;.001 -0.25 &lt;.001 BMI 0.14 &lt;.003 -0.04 NS -0.23 &lt;.001 Handgrip -0.17 &lt;.001 -0.03 NS 0.14 &lt;.05 Total power -0.14 &lt;.005 -0.05 NS 0.15 &lt;.001 * Back log trasformed
  • 15. &nbsp;
  • 16. &nbsp;
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  • 21. POLYMORPHISMS OF THE IGF-1 RESPONSE PATHWAY GENES AFFECT HUMAN LONGEVITY AND IGF-I PLASMA LEVELS: CUES FOR AN EVOLUTIONARY-CONSERVED MECHANISM OF LIFE-SPAN CONTROL Bonafè M * , Barbieri M *, Marchegiani F ^, Olivieri F^, Ragno E *, Giampieri C ^, Mugianesi E ^, Centurelli O^, Franceschi C * ^ and Paolisso G * * Department of Experimental Pathology- University of Bologna – via S. Giacomo 12, 40126-Bologna, Italy; * Department of Geriatricof Geriatric Medicine and Metabolic Diseases - – II University of Naples –Piazza Miraglia 2, 80138- Naples, Italy; ^ Italian National Research Centers on Aging (INRCA), via Birarelli 8, 60100 -Ancona, Italy Journal of Clinical Endocrinology and Metabolism, July 2003 in press
  • 22. WE INVESTIGATED the role of genetic variability at human loci which share similarities (human horthologs) with the genes which regulate the insulin/IGF-I response in C. elegans and D. melanogaster . namely: IGF-1R (34% protein sequence identity with C. elegans DAF-2) PIK3CB (27% protein sequence identity with C.elegans AGE-1) IRS-1 (30% protein sequence identity with D. melanogaster CHICO) FOXO1A (49% protein sequence identity with C. elegans DAF-16) EXPERIMENTAL APPROACH
  • 23. POLYMORPHISMS STUDIED <ul><li>IGF-1R Gene </li></ul><ul><li>+ 3174 , Codon 1013, Exon 16, G/A </li></ul><ul><li>PI3K CB Gene </li></ul><ul><li>-359 T/C </li></ul><ul><li>303 A/G </li></ul><ul><li>IRS-1 Gene </li></ul><ul><li>Codon 972, Exon1, G/A </li></ul><ul><li>FOXO1A Gene </li></ul><ul><li>+97347 , Intron 1, T/C </li></ul>
  • 24. SUBJECTS All subjects were neither diabetics nor affected by impaired fasting glucose No subject used drugs affecting insulin levels. CENTENARIANS N°218 Mean Age :98.0 ±4.31 ♂ =56; ♀=162 AGED PEOPLE N°278 Mean Age : 54.8 ±21.5 ♂ =76; ♀=202 Total N° 496
  • 25. &nbsp;
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  • 28. Simple correlation analysis between age and IGF-1 plasma levels in all study population (n= 496)
  • 29. Plasma free IGF-1 levels among different genotypes independently of age and gender. * Variation of the group means = p&lt;0.05
  • 30. RESULTS a) in the whole population polymorphisms at IGF-1R and PI3CKB loci are associated with significant changes in plasma IGF-1 levels; b) individuals bearing at least one allele A at IGF-1R locus (IGF-1R A+) are found at an increased proportion in long lived individuals and have lower free plasma IGF-I levels than A-, subjects c) Moreover, we found that genotype combination of an A allele at IGF-1R locus and a T allele at PI3CKB locus (A+/T+ subjects) is significantly increased in long lived individuals whilst A-/T- individuals have the highest free IGF-I plasma levels and show a trend to decrease among the long-lived people.
  • 31. Collectively, these data suggest that genetic VARIANTS OF IGF-1R and PI3CKB GENES involved in the intracellular IGF-I signaling pathway () jointly AFFECT two phenotypes: IGF-I PLASMA LEVELS AND LONGEVITY
  • 32. The highest national life expectancy observed for female, 1580 - present Max Plank Institute for Demography, Rostock, Germany, Annual Report 2001
  • 33. <ul><li>Antigenic Burden (AB) has a major impact on survival and frailty </li></ul><ul><li>AB depends on: </li></ul><ul><li>historical period where you live </li></ul><ul><li>geography (poor/dirty or rich/hygienized countries) </li></ul><ul><li>- social/economic status and education </li></ul>
  • 34. <ul><li>Parameters offering a direct or indirect measure of the lifelong antigenic load are available </li></ul><ul><li>They give us a synthetic measure of the lifelong attrition that each individual has undergone as a consequence of both his lifestyle and behaviour and its genetic tendency to develop and inflammatory phenotype . </li></ul>
  • 35. <ul><li>To our knowledge such markers (number of CD8+ memory or virgin T cells, expanded clones of memory/regulatory T cells, telomere length in peripheral blood lymphocytes, IL-6 plasma levels and genotype; IGF1 plasma levels; IGF-1R genotype) are the most powerful predictors of frailty and mortality in the elderly actually available </li></ul><ul><li>To this list TNF  , IL-10 and ApoE genotype and mtDNA haplogroups and mutations must be added </li></ul>
  • 36. &nbsp;

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