Delaying and Preventing Aging: What Therapies Work

Delaying and Preventing Aging:What Therapies WorkIris Thiele Isip Tan MD, FPCP, FPSEM

Clinical Associate Professor, UP College of MedicineSection of Endocrinology, Diabetes & Metabolism, Philippine General Hospital

3 March 2011

http://www.sxc.hu/photo/581797



Longevity & Disability Can death be delayed?

Can the course of disability and functional dependence be reversed?

Can disability and functional dependence be delayed?

Dominguez et al. The Aging Male, 2009

DHEA

Vitamin D

Growth hormone



http://www.sxc.hu/browse.phtml?f=view&id=424298







Adult candidates for GH treatment

Prior childhood GHD

Acquired GHD due to structural lesions or trauma

Idiopathic GHD

http://www.hghbodybuilding.com/About_hgh.asp

Evaluation and Treatment of Adult Growth Hormone Deficiency: An Endocrine Society Clinical Practice Guideline (2006)



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)





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





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)


http://www.drug3k.com/img2/humatrope_12179_4_%28big%29_.jpg





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







Adaptive? Less IGF-1 encourages apoptosis

and lessens risk of malignancy

Deficiency?

IGF-1 decreases with aging

↑ lean body mass 9% (4.7 kg)↓ adipose tissue mass 14% (3.5 kg)↑ lumbar vertebral bone density 1.6%↑ SBP and fasting glucose

No treatment (n=9) vs GH 0.03 mg/kg BW/week (n=12) x 6 months

21 healthy men 61-81 yserum IGF-1 below normal for young men

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IGF-1 level doubled

NOT a randomized, blind study

Rudman et al. NEJM 1990;323:1-6

Weekly dose ~2x as high as for men with GH deficiency

StudyInitial daily GH dose (ug/kg/d)

Duration (months)

Positiveeffects

Adverse effects

Rudman 1990

Holloway 1994

Papadakis 1996

Johannson 1997

Lange 2002

Franco 2005

12.9 6increase lean mass

increase BMDhypertension

hyperglycemia

43 6decrease fat massincrease lean mass

edemacarpal tunnel

syndrome

12.9 6decrease fat massincrease lean mass

edema arthralgias

9.5 9decrease fat mass

improve insulin sensitivitydecrease cholesterol

edemacarpal tunnel syndrome

arthralgias

12.9 (+ exercise)

3decrease fat massincrease lean mass

edemacarpal tunnel syndrome

7.8 12decrease fat mass

improve insulin sensitivitydecrease cholesterol

edemahyperglycemia

Main human clinical studies with rhGH treatment in healthy elderly

Giordano R. Hormones 2008;7(2):133-139

rhGH treatmentCan death be delayed?

Reduced GH and IGF-1 levels associated with 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

http://upload.wikimedia.org/wikipedia/commons/7/71/Lab_mouse_mg_3157.jpg

Giordano R. Hormones 2008;7(2):133-139





RR 4.3 for prostate cancer in 152 healthy men with IGF-1 in the highest quartile vs men in the lowest IGF-1 quartile

rhGH treatmentCan death be delayed?


Older age is associated with an increased incidence of cancer

Melmed GY et al. Clin Gastroenterol Hepatol 2008;6(3):360-3

Case report68/M with Crohn’s colitis on rhGH x 7 y who developed aggressive, metastatic color cancer

Chan JM et al. Science 1998;279:563-6



Increase in lean body and muscle mass ? fluid retention

Reduction in body fat

↓ total cholesterolno 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

rhGH treatmentCan disability and functional dependence be delayed?

http://www.sxc.hu/photo/833821 Giordano R. Hormones 2008;7(2):133-139



DHEA

Vitamin D

Growth hormone




Not recommended at this time unless with GHD







Hypovitaminosis D

Less vitamin D precursor generation in aging skin

Reduced outdoor physical activities and immobility

Avoidance of sunlight and use of sun protective agents

http://www.flickr.com/photos/kitoy/2193993891/

Lanske B & Razzaque MS. J Nutri Biochem 2007; 18(12):771-7



Hypovitaminosis D

Low 25(OH)D associated with hypertension, diabetes, insulin resistance, elevated BMI and incident hypertension

Ecological studies

CVD events are higher in the winter when vitamin D levels are lower

Cancer survival is better if the cancer is diagnosed in the summer when vitamin D levels are higher


Melamed ML. Arch Intern Med 2008;168(15):1629-37





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%

Test association of low 25(OH)D levels with all cause, cancer and CVD mortality Participant vitamin D levels collected 1988-1994Individuals passively followed for mortality through 2000

13,331 nationally representative adults >20 y from NHANES III

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Low serum 25(OH)D and mortality

Low 25(OH)D not just a marker for poor general health

Association of low 25(OH)D with mortality was strongest in those without CVD, hypertension and diabetes

Association between 25(OH)D and mortality more pronounced among women

? estrogen and 25(OH)D

Melamed ML. Arch Intern Med 2008;168(15):1629-37 http://www.flickr.com/photos/kitoy/2193993891/



Meta-analysis (18 RCTS, n=57,311)literature up to Nov 2006Mean daily vitamin D dose 528 IU (400-833 IU)

Randomized trials testing impact of vitamin D supplementation (D2 or D3) on any health condition

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Autier P & Gandini S. Arch Intern Med 2007;167(16):1730-37

Intake of ordinary doses of vitamin D supplements seems to be associated with decreases in total mortality rates

Autier P & Gandini S. Arch Intern Med 2007;167(16):1730-37

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

klotho-deficient mutant miceincreased production of vitamin D

exhibit premature agingatherosclerosis, emphysema, ostepenia/osteoporosis,

hypogonadism, soft tissue calcifications and generalized atrophy of organs

Takahashi Y. PNAS 2000; 97(23):12407-8

Lanske B & Razzaque MS. J Nutri Biochem 2007; 18(12):771-7

http://www.flickr.com/photos/archaicwarrior/613707342/



Association of 25(OH)D with current physical performance and its decline over 3 y

Cohort within Longitudinal Aging Study Amsterdam1234 men and women >65 y (cross-sectional)979 (79%) for longitudinal analysis

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Wicherts IS et al. JCEM 2007;92:2058-65

Serum 25(OH)D <20 ng/mL associated with poorer physical performance and a greater decline in physical performance in older men and women

Serum 25(OH)D and Physical Performance Score


Adjusted for age, gender, number of chronic diseases, degree of urbanization, BMI and alcohol consumption

Meta-analysis: 8 double blind RCTs (n=2426)(literature search up to 2008)Oral D3 or D2 or 1,25-dihydroxyvitamin D3

Older individuals mean age >65 y

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Bischoff-Ferrari HA et al. BMJ 2009;339:b3692

Risk of falling

Text

Supplemental vitamin D

[700-1000 IU/day] reduced the risk of falling among older individuals by 19%

Pooled RR 0.81 (95%CI 0.71 to 0.92)


TrialVit D dose/ preparation

ug (IU)/d

Duration of trial

25(OH)D level achieved

nmol/LOutcome

Muscle performance

SatoPfeiffer

Bischoff

25(1000) D220 (800) D320 (800) D3

3 y2 mo3 mo

846666

+++

Falls

BischoffBroe

FlickerGrant

17.5 (700) D320 (800) D220 (800) D220 (800) D3

3 y5 mo2 y5 y

9975NA62

+++

Null

Dawson-Hughes, Am J Clin Nutr 2008;88(suppl):573S-40S

Randomized controlled trials Vitamin D and the Risk of Falls

Potential candidates as functional indicators

Setting the EAR* for Vitamin D

* Estimated Average Requirement

Indicator Indicator of Suboptimal Status

Calciotropic function

Parathyroid hormone Stimulated level of PTH

Calcium absorptionPercentage absorption of Ca improves when Vit D provided

Fracture riskIncrease in fracture risk relative to adequate Vit D status

Muscle strength Muscle strength tests

Serum calcium and phosphorus

Relative hypocalcemia and hypophosphatemia

Bone turnover markers

Increased bone resorption and decreased bone formation

Whiting & Calvo, J Nutr 2005;135:304-9

Serum 25(OH)D

<25 nmol/L 25-75 nmol/L >75 nmol/L

Deficiency Insufficiency Sufficiency

Dawson-Hughes B, Am J Clin Nutr 2008:88(suppl);537S-40S

Variability of vit D concentration by geographical location

Differences in assay methodology

Optimal level of 25(OH)D 30 ng/mL determined in a Caucasian population

What cut-off value defines low vit D status?

DHEA

Vitamin D

Growth hormone





Can be given, but need more data on correct dosing







Dhatariya KK et al. Mayo Clin Proc 2003;78:1257-73

DHEAS assay

Cambridge General Practice Health Study963 men and 1171 women, 65-76 y surveyed in 1991-1995 and followed up until Aug 2000

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All-cause and CVD mortality highest in the lowest DHEAS quartile in men; no difference in upper three quartiles

Trivedi DP & Khaw KT. JCEM 2001; 86(9):4171-7

No significant association of DHEAS and mortality in women


Men


Women

2-y, placebo-controlled, randomized, double-blind29 on DHEA, 27 on testosterone, 31 on placebo

87 elderly men with low DHEAS levels and bioavailable testosterone

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P

No significant difference in quality of life measured by the HSQ Physical/Mental Component Scales

Nair KS et al. NEJM 2006; 355:1647-59

oral DHEA 50 mg/d x 1 yeardouble-blind, placebo-controlled

DHEAge Study280 healthy ambulatory/independent women 60-80 y

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Percheron G et al. Arch Intern Med 2003;163:720-7

Restored DHEAS levels to normal range (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)

SourceSubjects

(Age range, y)DHEA

Duration, mo

Trial DesignDHEAS

measured

Yen et al, 1995

Diamond et al, 1996

Morales et al, 1998

Percheron et al, 2003

8 men and 8 women (50-65)

Oral, 100 mg/d

6Crossover placebo-controlled

Yes

15 women (60-70)

Percutaneous 3-5 g/d of a 10% cream

12Crossover placebo-controlled

No

10 women and 9 men

(50-65)

Oral, 100 mg/d

6

Crossover double-blind

placebo-controlled

Yes

140 men and 140 women

(60-80)

Oral, 50 mg/d

12Double-blind

placebo- controlled

Yes

Percheron G et al. Arch Intern Med 2003;163:720-7

Characteristics of Studies Including Results of DHEA Treatment on Muscle Function

Randomized, placebo-controlledoral DHEA 50 mg daily x 1 year

DAWN Trial225 health adults aged 55-85 y

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von Muhlen et al. Osteoporos Int 2008;19(5):699-707

Restored DHEAS levels to range for young adultsModest and selective beneficial effect on BMD (lumbar spine) and bone resorption in women but provides no benefit for men

DHEA

Vitamin D

Growth hormone





Can be given, but need more data on correct dosing

Not recommended at this time







!ank Y"http://www.endocrine-witch.net

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Delaying and Preventing Aging: What Therapies Work

Health & Medicine

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