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Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
Delaying and Preventing Aging: What Therapies Work
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Delaying and Preventing Aging: What Therapies Work

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Presentation at 2011 Philippine Society for Aging Male (PhiSSAM) annual convention

Presentation at 2011 Philippine Society for Aging Male (PhiSSAM) annual convention

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  1. 3 March 2011 Delaying and Preventing Aging: What Therapies Work Iris Thiele Isip Tan MD, FPCP, FPSEM Clinical Associate Professor, UP College of MedicineSection of Endocrinology, Diabetes & Metabolism, Philippine General Hospital http://www.sxc.hu/photo/581797
  2. Longevity & Can death be delayed?Disability Can the course of disability and functional dependence be reversed? Can disability and functional dependence be delayed? Dominguez et al. The Aging Male, 2009
  3. Growth hormonehttp://www.sxc.hu/photo/529230 Vitamin D http://www.sxc.hu/browse.phtml?f=view&id=424298 DHEAhttp://www.sxc.hu/photo/607213
  4. Adult candidatesfor GH treatment Prior childhood GHD Acquired GHD due to structural lesions or trauma Idiopathic GHD Evaluation and Treatment of Adult Growth Hormone Deficiency: An Endocrine Society Clinical Practice Guideline (2006) http://www.hghbodybuilding.com/About_hgh.asp
  5. GH for adults withdocumented GH deficiency Insulin tolerance and GHRH- arginine tests GHRH-arginine may be misleading in clearly established recent (<10 y) hypothalamic causes of suspected GHD i.e. irradiation Provocative testing optional if with multiple hormone deficiencies (>3 pituitary axes) Evaluation and Treatment of Adult Growth Hormone Deficiency: An Endocrine Society Clinical Practice Guideline (2006) http://www.hghbodybuilding.com/About_hgh.asp
  6. GH for adults withdocumented GH deficiency Normal IGF-1 level does not exclude the diagnosis of GHD but makes provocative testing mandatory Low IGF-1 level, in the absence of catabolic conditions and liver disease indicates severe GHD May be useful in identifying patients who may benefit from treatment Evaluation and Treatment of Adult Growth Hormone Deficiency: An Endocrine Society Clinical Practice Guideline (2006) http://www.hghbodybuilding.com/About_hgh.asp
  7. GH regimen for adults withdocumented GH deficiency Individualize dose (not weight-based) Initiate adults 30-60 y with 300 ug/d and increase by 100-200 ug every 1-2 months Start lower (100-200 ug/d) and increase more slowly for older patients (>60 y) Evaluation and Treatment of Adult Growth Hormone Deficiency: http://www.drug3k.com/img2/ An Endocrine Society Clinical Practice Guideline (2006) humatrope_12179_4_%28big%29_.jpg
  8. GH regimen for adults withdocumented GH deficiency Titrate GH dose according to clinical response, side effects and IGF-1 levels (age-adjusted reference) Clinical benefits apparent at >6 mos Monitor q 1-2 months during dose titration and semiannually thereafter Evaluation and Treatment of Adult Growth Hormone Deficiency: http://www.drug3k.com/img2/ An Endocrine Society Clinical Practice Guideline (2006) humatrope_12179_4_%28big%29_.jpg
  9. Adaptive?Less IGF-1 encourages apoptosis and lessens risk of malignancy Deficiency?IGF-1 decreases with aging
  10. P21 healthy men 61-81 yserum IGF-1 below normal for young men NOT a randomized, blind studyINo treatment (n=9) vs GH 0.03 mg/kgBW/week (n=12) x 6 monthsWeekly dose ~2x as high as for men with GH deficiencyO IGF-1 level doubled↑ lean body mass 9% (4.7 kg)↓ adipose tissue mass 14% (3.5 kg)↑ lumbar vertebral bone density 1.6%↑ SBP and fasting glucose Rudman et al. NEJM 1990;323:1-6
  11. Main human clinical studies with rhGH treatment in healthy elderly Initial daily Duration Positive Adverse Study GH dose (months) (ug/kg/d) effects effects Rudman increase lean mass hypertension 12.9 6 1990 increase BMD hyperglycemia Holloway decrease fat mass edema 43 6 carpal tunnel 1994 increase lean mass syndromePapadakis decrease fat mass edema 12.9 6 1996 increase lean mass arthralgias decrease fat mass edemaJohannson 9.5 9 improve insulin sensitivity carpal tunnel syndrome 1997 arthralgias decrease cholesterol Lange 12.9 decrease fat mass edema 3 2002 (+ exercise) increase lean mass carpal tunnel syndrome decrease fat mass Franco edema 7.8 12 improve insulin sensitivity 2005 hyperglycemia decrease cholesterol Giordano R. Hormones 2008;7(2):133-139
  12. Longevity & Can death be delayed?Disability Can the course of disability and functional dependence be reversed? Can disability and functional dependence be delayed? Dominguez et al. The Aging Male, 2009
  13. Reduced GH and IGF-1rhGH treatment levels associated withCan death be delayed? significant increases in both average and maximal lifespan GH-resistant & GH-deficient mutant mice live longer! Transgenic mice that produce supra-physiologic levels of GH for age have markedly reduced lifespan Giordano R. Hormones 2008;7(2):133-139 http://upload.wikimedia.org/wikipedia/commons/ 7/71/Lab_mouse_mg_3157.jpg
  14. rhGH treatment RR 4.3 for prostate cancerCan death be delayed? in 152 healthy men with IGF-1 in the highest quartile vs men in the lowest IGF-1 quartile Chan JM et al. Science 1998;279:563-6 Case report 68/M with Crohn’s colitis on rhGH x 7 y who developed aggressive, metastatic color cancer Melmed GY et al. Clin Gastroenterol Older age is associated with an Hepatol 2008;6(3):360-3 increased incidence of cancer http://www.sxc.hu/photo/707124
  15. Increase in lean body andrhGH treatment muscle massCan disability and functional ? fluid retentiondependence be delayed? Reduction in body fat ↓ total cholesterol no significant effect on LDL, HDL or triglycerides No effects on muscle strength, bone mass, functional capacity and glucose metabolism No significant difference bet GH + lifestyle intervention vs GH alone http://www.sxc.hu/photo/833821 Giordano R. Hormones 2008;7(2):133-139
  16. Growth hormone Not recommended at this time unless with GHDhttp://www.sxc.hu/photo/529230 Vitamin D http://www.sxc.hu/browse.phtml?f=view&id=424298 DHEAhttp://www.sxc.hu/photo/607213
  17. Hypovitaminosis DLess vitamin D precursorgeneration in aging skinReduced outdoor physicalactivities and immobilityAvoidance of sunlight and useof sun protective agents Lanske B & Razzaque MS. J Nutri Biochem 2007; 18(12):771-7 http://www.flickr.com/photos/kitoy/2193993891/
  18. Hypovitaminosis DLow 25(OH)D associated with hypertension,diabetes, insulin resistance, elevated BMI http://www.flickr.com/photos/ kitoy/2193993891/and incident hypertensionEcological studiesCVD events are higher in the winter whenvitamin D levels are lowerCancer survival is better if the cancer isdiagnosed in the summer when vitamin Dlevels are higher Melamed ML. Arch Intern Med 2008;168(15):1629-37
  19. Longevity & Can death be delayed?Disability Can the course of disability and functional dependence be reversed? Can disability and functional dependence be delayed? Dominguez et al. The Aging Male, 2009
  20. P13,331 nationally representative adults>20 y from NHANES IIIITest association of low 25(OH)D levelswith all cause, cancer and CVD mortalityParticipant vitamin D levels collected 1988-1994Individuals passively followed for mortality through 2000O Lowest quartile of 25(OH)D level <17.8 ng/ mL independently associated with all-cause mortality in the general population ↑26% all-cause mortality (95% CI 1.08-1.46) Population attributable risk 3.1% Melamed ML. Arch Intern Med 2008;168(15):1629-37
  21. Melamed ML. Arch Intern Med 2008;168(15):1629-37
  22. Low serum 25(OH)Dand mortalityLow 25(OH)D not just a marker forpoor general health Association of low 25(OH)D with mortality was strongest in those without CVD, hypertension and diabetesAssociation between 25(OH)Dand mortality more pronouncedamong women ? estrogen and 25(OH)D Melamed ML. Arch Intern Med 2008;168(15):1629-37 http://www.flickr.com/photos/kitoy/2193993891/
  23. Melamed ML. Arch Intern Med 2008;168(15):1629-37
  24. PRandomized trials testing impact ofvitamin D supplementation (D2 or D3) onany health conditionIMeta-analysis (18 RCTS, n=57,311)literature up to Nov 2006Mean daily vitamin D dose 528 IU (400-833 IU)OIntake of ordinary doses of vitamin Dsupplements seems to be associated withdecreases in total mortality rates Autier P & Gandini S. Arch Intern Med 2007;167(16):1730-37
  25. SRR for all-cause mortality 0.93 (NV 0.87-0.99)Most trials were of frail elderly people at high risk of fall or of low-energy fracture often with low serum 25(OH)D Autier P & Gandini S. Arch Intern Med 2007;167(16):1730-37
  26. Melamed ML. Arch Intern Med 2008;168(15):1629-37
  27. Lanske B & Razzaque MS. J Nutri Biochem 2007; 18(12):771-7 klotho-deficient mutant mice increased production of vitamin D exhibit premature aging atherosclerosis, emphysema, ostepenia/osteoporosis, hypogonadism, soft tissue calcifications and generalized atrophy of organshttp://www.flickr.com/photos/archaicwarrior/613707342/ Takahashi Y. PNAS 2000; 97(23):12407-8
  28. Longevity & Can death be delayed?Disability Can the course of disability and functional dependence be reversed? Can disability and functional dependence be delayed? Dominguez et al. The Aging Male, 2009
  29. PCohort within Longitudinal Aging Study Amsterdam1234 men and women >65 y (cross-sectional)979 (79%) for longitudinal analysisIAssociation of 25(OH)D with current physicalperformance and its decline over 3 yOSerum 25(OH)D <20 ng/mL associated withpoorer physical performance and a greaterdecline in physical performance in older menand women Wicherts IS et al. JCEM 2007;92:2058-65
  30. Serum 25(OH)D and Physical Performance Score Adjusted for age, gender, number of chronic diseases, degree of urbanization, BMI and alcohol consumption Wicherts IS et al. JCEM 2007;92:2058-65
  31. Wicherts IS et al. JCEM 2007;92:2058-65
  32. POlder individuals mean age >65 yIMeta-analysis: 8 double blind RCTs (n=2426)(literature search up to 2008)Oral D3 or D2 or 1,25-dihydroxyvitamin D3ORisk of falling Bischoff-Ferrari HA et al. BMJ 2009;339:b3692
  33. Supplemental vitamin D [700-1000 IU/day]Text reduced the risk of falling among older individuals by 19% Pooled RR 0.81 (95%CI 0.71 to 0.92) Bischoff-Ferrari HA et al. BMJ 2009;339:b3692
  34. Bischoff-Ferrari HA et al. BMJ 2009;339:b3692
  35. Randomized controlled trials Vitamin D and the Risk of Falls Vit D dose/ 25(OH)D level Duration Trial preparation achieved Outcome of trial ug (IU)/d nmol/LMuscleperformance Sato 25(1000) D2 3y 84 + Pfeiffer 20 (800) D3 2 mo 66 + Bischoff 20 (800) D3 3 mo 66 +Falls Bischoff 17.5 (700) D3 3y 99 + Broe 20 (800) D2 5 mo 75 + Flicker 20 (800) D2 2y NA + Grant 20 (800) D3 5y 62 Null Dawson-Hughes, Am J Clin Nutr 2008;88(suppl):573S-40S
  36. Potential candidates as functional indicatorsSetting the EAR* for Vitamin D Indicator Indicator of Suboptimal StatusCalciotropic functionParathyroid hormone Stimulated level of PTH Percentage absorption of Ca improvesCalcium absorption when Vit D provided Increase in fracture risk relative toFracture risk adequate Vit D statusMuscle strength Muscle strength testsSerum calcium and Relative hypocalcemia andphosphorus hypophosphatemiaBone turnover Increased bone resorption andmarkers decreased bone formation* Estimated Average Requirement Whiting & Calvo, J Nutr 2005;135:304-9
  37. What cut-off valuedefines low vit D status?Serum 25(OH)D<25 nmol/L 25-75 nmol/L >75 nmol/LDeficiency Insufficiency SufficiencyOptimal level of25(OH)D 30 ng/mL Variability of vit D concentrationdetermined in a by geographical locationCaucasian population Differences in assay methodology Dawson-Hughes B, Am J Clin Nutr 2008:88(suppl);537S-40S
  38. Growth hormone Not recommended at this time unless with GHDhttp://www.sxc.hu/photo/529230 Vitamin D Can be given, but need more data on correct dosing http://www.sxc.hu/browse.phtml?f=view&id=424298 DHEAhttp://www.sxc.hu/photo/607213
  39. Dhatariya KK et al. Mayo Clin Proc 2003;78:1257-73
  40. Dhatariya KK et al. Mayo Clin Proc 2003;78:1257-73
  41. Longevity & Can death be delayed?Disability Can the course of disability and functional dependence be reversed? Can disability and functional dependence be delayed? Dominguez et al. The Aging Male, 2009
  42. PCambridge General Practice Health Study963 men and 1171 women, 65-76 y surveyed in1991-1995 and followed up until Aug 2000IDHEAS assayO All-cause and CVD mortality highest in the lowest DHEAS quartile in men; no difference in upper three quartiles No significant association of DHEAS and mortality in women Trivedi DP & Khaw KT. JCEM 2001; 86(9):4171-7
  43. MenTrivedi DP & Khaw KT. JCEM 2001; 86(9):4171-7
  44. WomenTrivedi DP & Khaw KT. JCEM 2001; 86(9):4171-7
  45. P87 elderly men with low DHEAS levelsand bioavailable testosteroneI2-y, placebo-controlled, randomized, double-blind29 on DHEA, 27 on testosterone, 31 on placeboONo significant difference in quality of lifemeasured by the HSQ Physical/MentalComponent Scales Nair KS et al. NEJM 2006; 355:1647-59
  46. Longevity & Can death be delayed?Disability Can the course of disability and functional dependence be reversed? Can disability and functional dependence be delayed? Dominguez et al. The Aging Male, 2009
  47. PDHEAge Study280 healthy ambulatory/independent women 60-80 yIoral DHEA 50 mg/d x 1 yeardouble-blind, placebo-controlled Restored DHEAS levels to normal rangeO (age 20-50y) No beneficial effect on muscle strength (handgrip and isometric/isokinetic knee muscle strength) or in muscle and fat cross-sectional areas (thigh) Percheron G et al. Arch Intern Med 2003;163:720-7
  48. Characteristics of Studies Including Results of DHEA Treatment on Muscle Function Subjects Duration, DHEAS Source DHEA Trial Design (Age range, y) mo measured 8 men and 8 Crossover Yen et al, Oral, women 6 placebo- Yes 1995 100 mg/d controlled (50-65) Percutaneous CrossoverDiamond et 15 women 3-5 g/d of a 12 placebo- No al, 1996 (60-70) 10% cream controlled 10 women CrossoverMorales et Oral, double-blind and 9 men 6 placebo- Yes al, 1998 100 mg/d (50-65) controlled 140 men and Double-blindPercheron Oral, 140 women 12 placebo- Yeset al, 2003 50 mg/d controlled (60-80) Percheron G et al. Arch Intern Med 2003;163:720-7
  49. PDAWN Trial225 health adults aged 55-85 yIRandomized, placebo-controlledoral DHEA 50 mg daily x 1 yearO Restored DHEAS levels to range for young adults Modest and selective beneficial effect on BMD (lumbar spine) and bone resorption in women but provides no benefit for men von Muhlen et al. Osteoporos Int 2008;19(5):699-707
  50. Growth hormone Not recommended at this time unless with GHDhttp://www.sxc.hu/photo/529230 Vitamin D Can be given, but need more data on correct dosing http://www.sxc.hu/browse.phtml?f=view&id=424298 DHEA Not recommended at this timehttp://www.sxc.hu/photo/607213
  51. !ank Y"http://www.endocrine-witch.net

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