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Vitamins & Successful Aging:Promising or Empty Promises?

Hope Barkoukis, PhD, RD, LDSchool of Medicine

Case Western Reserve UniversityHope.Barkoukis@case.edu or Hope1215@aol.com

Vitamin“hero”

•24% ≥ 65 are obese

•22%participate in regular physical activity

•54% of leisure time is spent watching TV – (average 6.5 hours daily)

Demographics:20% over age 65 by 2030

CDC Nat’l CenterHealth Statistics, 2006

Most prevalent chronic diseases: heart disease, hypertension, arthritis

NO KNOWN MARKERS TO ASSESS OUR

RATE OF AGING

MASKING AGE CHANGES(COSMETICALLY),NOT THE SAME ASINTERVENING IN AGING PROCESS!!

No accepted therapy to halt

or reverse agingProcess*

• *Caloric restriction

June 13, 2005 (Scotland) Fauja Singh

• Oldest marathon relay team (5 man)• Combined age = 397 years• Placed 730th of the 912 teams (4hr 16min 24sec)

Universal agreement: PA slows aging

process94- World’s oldestmarathoner

Mobility:‘superior marker of overall health status’

“Mobility •is a marker of health status•superior to any other measure•one of the main determinants of QOL in old age”

•Director of BaltimoreLongitudinal Study on Aging-L. Ferrucci

Journal of Geriatrics. 63A(12):1416, 2008- Baltimore Longitudinal Study on Aging (BLS) (1958-current)

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A bit of background- use of vitamin

supplements in older adult……Sloan, 2009

• No universal descriptor for ‘older adult’

• Nearly all created wealth past decade ≥ 55yo

• Aged 65-74 most frequent age group user of DS and most likely to practice preventive medicine

• Twice as likely, (as any other age group) to take fish oil, omega 3, Vitamins C, E, B12, D

Interruption in sourceInterruption in sourceInterruption in sourceInterruption in sourceRRRReduction in body storageeduction in body storageeduction in body storageeduction in body storage

Impairments in biochemical functioningImpairments in biochemical functioningImpairments in biochemical functioningImpairments in biochemical functioning

Alteration in function/morphologyAlteration in function/morphologyAlteration in function/morphologyAlteration in function/morphology

Result: Clinical Manifestations*Result: Clinical Manifestations*Result: Clinical Manifestations*Result: Clinical Manifestations*

*Clinical manifestations target every organ*Clinical manifestations target every organ*Clinical manifestations target every organ*Clinical manifestations target every organ

STAGES OF VITAMIN DEFICIENCY:

Determine: too little, too much,Should be adequate?

Primary observation:� Nutrient supply� Supplements

Quantitative determination-food, beverages, supplements-OTC & RX drugs

Are there secondary factors to consider? Health/medical

History, socio-economic issues, etc, etc

Concomitant considerations: increased need, lossdecreased availabilitydecreased absorption

STATUS DETERMINATION

Determining nutrient reserve status: • stable, • increased, • decreased

Consider: plasma, tissues

Quantitative analysis ofBlood, urine, tissues, Vitamin/metabolites

Observe gradual alteration in levels?Stability of plasma, urine levels, etc

STATUS DETERMINATION: TRENDING…

Any changes in metabolic Pre-Clinical Quantitative analysis functioning? findings of enzyme activity

functional parameters

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WHAT INDICATOR IS BEST FOR THE GIVEN VITAMIN STATUS DETERMINATION?

BASED UPON SPECIFIC INDICATORS

•INDICATORS VARY PER VITAMIN AND LIFE CYCLE•INDICATORS MAY ALSO VARY BASED ON FACTORS SUCH AS

“SMOKER” OR NON SMOKER

CONCEPT OF ADEQUACY •HAS EVOLVED FROM AMOUNT OF

VITAMIN TO MAINTAIN A DEFINED LEVEL OF THAT VITAMINAS NEEDED TO MEET A SPECIFIC CRITERIA↓↓↓↓•INCLUDE CONCEPT OF RISK REDUCTION FROM CHRONIC

DISEASE, AND OPTIMAL BODY POOL/STORES

BESTGoodLimited

Sensitivity of markers to assess status: Sensitivity of markers to assess status: Sensitivity of markers to assess status: Sensitivity of markers to assess status:

A, E, B6, Biotin, Pantothenic Acid, Niacin, C, B1, B2, B12, Folate, K, DA, E, B6, Biotin, Pantothenic Acid, Niacin, C, B1, B2, B12, Folate, K, DA, E, B6, Biotin, Pantothenic Acid, Niacin, C, B1, B2, B12, Folate, K, DA, E, B6, Biotin, Pantothenic Acid, Niacin, C, B1, B2, B12, Folate, K, D

Functional markers to assess status: Functional markers to assess status: Functional markers to assess status: Functional markers to assess status:

B1B1B1B1---- enzyme assay, B2enzyme assay, B2enzyme assay, B2enzyme assay, B2----enzyme assay, B12enzyme assay, B12enzyme assay, B12enzyme assay, B12---- MMA, K MMA, K MMA, K MMA, K

AAAA

Plasma values to assess status: Plasma values to assess status: Plasma values to assess status: Plasma values to assess status:

A*, B6*, folate, D, E*, CA*, B6*, folate, D, E*, CA*, B6*, folate, D, E*, CA*, B6*, folate, D, E*, C---- (leucocyte) (leucocyte) (leucocyte) (leucocyte)

Urine values to assess status: Urine values to assess status: Urine values to assess status: Urine values to assess status:

Niacin, biotin, pantothenic acid Niacin, biotin, pantothenic acid Niacin, biotin, pantothenic acid Niacin, biotin, pantothenic acid

BODY RESERVES OF VARIOUS VITAMINS:

• Vitamin Mean length of reserves

– Vitamin B12: 3-5 years

– Vitamin A: 1 – 2 years

– Thiamin & Biotin: 4-10 days

– D,E,K, C : 2 to 6 weeks

– Folate : 3 to 4 months

Source: Modern Nutrition in Health & Disease, most recent edition

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Current NAS recommendations: older adult & increased vitamin

requirements:

• Vitamin B 12

• Vitamin D

• Vitamin B6

• Not hormone therapy or high doses of

vitamins for anti-aging*

• Length of telomeres

below a CERTAIN fixed number that is

critically needed for cell function causes

irreversible cell senescence

•Called: Te or “critical telomere length”

•Accumulation of these “critically shortened

telomeres = senescence, then

death

•Shorter T = ↑↑↑↑ mortality

Telomeres: Global marker of ‘aging’

Global marker of ‘aging’ and vitamin intakeXu, Q, et al Multivitamin use & telomere length

AJCN 89:1857, 2009

• 35-74 yo females

• Sisters of breast ca patients

• N=586

• 2004-2009

• FFQ-Block, urine, blood, detailed health screening

• Kcal adjustments between users & non-users of Multi-vitamins & B complex

• p=N/S for age, perceived health, health, physical activity

• P= < .05 education, smoking between users and non

Increased frequency of vitamin Supplement use significantly increasedTelomere length- in all subjects & sub-groups

• Increased average TL =~ 9.8 years

p=n/s

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Global Anti-Aging market: 162 billion $ 2013: 274.5 billion $

3 Core categories of Anti-Aging Market

Disease prevention &

Reactivecare

Fitness &regeneration

Appearance and

Body shaping

• American Association Anti-Aging Medicine• “Conspiracy theory”•Major force in initiating ‘anti-aging’ supplementation

A4M

• Not recognized by any established medical association

• AMA

• NIA- created a fact sheet to dispel anti-aging rhetoric

• ‘Serious threat to scientific research on aging’

• ~ 20,000 practitioners

• Very controversial

• Practical immortality

A4M

• New health care paradigm- increase life span

• Aging from physiologic dysfunction

• Anti-Aging transformation

• Hormone replacement tx, high levels of supplemental anti-oxidants & vitamins, life style, diet, exercise

• Sponsor: World Anti-Aging Congress

• International Journal Anti-Aging Medicine

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“Hormesis”‘dose’ matters: dose either has a favorable

or harmful biologic effect

• Lower dose has opposite effect of a higher dose

• Controversial in other areas but not in aging literature

• Results in response curve – J or U shaped curve

Examples of ‘negative’ effects on adult after SUPPLEMENTAL anti-oxidants

“Exercise induced oxidative stress causes adaptive responses promoting endogenous anti-oxidant defense capacity.

Supplementation w antioxidants,( C& E), may preclude these health promoting effects of exercisein humans”. Proc Nat’l Acad Sci USA May 26;106(21):8665, 2009

Anti-oxidants do not prevent post-ex peroxidation &may delay muscle recovery. Med Sci Sports Exerc. Sept 41(9):1752, 2009

Mortality in RCT of anti-oxidant supplementation for primary & secondary prevention: systematic review &

meta analysis. JAMA:297(8) 842, 2007

• Random effects meta-analysis & meta regression for co-variates, RCT, using vitamin C, selenium, beta carotene, vitamin E- either alone or in combination

• Vitamins:

– Vitamin C, p=N/S for mortality, but

– Vitamin E (RR= 1.04);

– Vitamin A (RR=1.16); beta carotene (RR=1.07) significantly increased mortality in low bias trials, where total n=180,938

Anti-oxidant vitamins –encourage food sources, too premature to encourage supplemental AO vitamins for older, active adult at this time

Antioxidants: what role do they play in physical activity & health? AJCN 72:637,2000

Anti-oxidants and older adult?

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8 isomers of Vitamin E: tocopherols: oils, nuts, seeds; tocotrienols: oat, rye, wheat germ, barley, rice bran

Natural E: 1.5IU/mg; Synthetic, all rac αααα 1.1IU/mg

Vitamin E ‘family’ Summary: where are we with E?

• Physician’s Health Study II, 1997-2007, RCT, supplemental E (400 IU* every other day, 500mg C daily) (*synthetic)

• N=14,641, 5.5% had CV disease at randomization

• Neither vitamin had significant effect on total mortality, E increased risk of stroke (p=.04)

• Sesso, JAMA 300(18):2123, 2008

• Woman’s Health Study, 1992-2004, RCT, 600IU* (natural form) or aspirin, placebo, alternate days

• N=39,876, healthy, ≥45yo

• No CVD prevention benefit, or cancer, or total mortality

• Lee, JAMA 294(1):56,2005

Where are we with E?

• 2003-2005 3 meta-analyses done on safety of E supplemental- none on healthy

• Vivekananthan, 2003; Bjelakovic, 2004, Miller, 2005– V: CVD mortality, events, all cause mortality;

7 trials, 81,000, dose range: 50-800IU, 1.4-6.3 years. No improvement.

– Author: those w CVD not use supplemental E, further funding discontinued.

– Vivekananthan, Lancet, 361:2017, 2003

Where are we with E?

• Bjelakov: 14 trials; effect on GI cancers, 1-12 years, doses 30mg to 600mg, 70,000 =n– Conclusions: no effect on preventing GI

cancers

• Miller: 19 trials, elderly, chronic co-morbidities, (8= less than 400IUs, 11 more). – All cause mortality significantly increased with

doses over 800 IU

Where are we with E & CVD?

• All epidemiologic cohort studies observed E intakeassociated with significant reduction in CVD Rimm, 1993, Stampfer, 1993

– Endpoints: non-fatal & fatal CV disease

– Prabhat, Annals Internal Medicine, 123 (11);860,1995

• RCT- do NOT support this observation– No significant CV risk

reduction

– Supplementation MORE likely to increase all cause mortality in supplemented group

– NO data to support supplemental use of E for CVD

– Stroke-meta-analysis 13 studies, both forms of E, lack of benefit in stroke prevention Bin, Thromb Haemost 105:1,

2011

– Lichtenstein, J Lipid Research 50:S429, 2009

Timing is everything….

• In all animal data, vitamin E protective when E given before histologic evidence of intimal or fatty streak formation

• Observational studies of CV benefit, again no evidence of vascular disease Rimm, 2003; Lancet

361:2017, 2003

• Dotan, 2009, using computer model to review existing data- some sub-populations might benefit, no benefit for those already at risk Dotan, Arterioscler Thromb Vasc Biol 9/1:29(9):1304,2009

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Still promising looking ahead….

• Tocopherol isomers each differ in anti-tumorgenic ability

• Tocopherols: δδδδ and γγγγmore potent than αααα

• Tocotrienols more potent than tocopherols for anti-tumor activity

• αααα tocopherol most potent anti-oxidant, but incapable of inducing apoptosis

• Order of efficacy: delta >>>>gamma >>>>alpha

B vitamins & CV risk: No data support of folic

acid &/or B vitamins for CVD risk reduction Lichtenstein, J Lipid Research 50:S429, 2009

• RCT- effectively lowered homocysteine demonstrated no significant effect on CV events nor all cause mortality

• Animal data, retrospective studies in humans & case studies:

– Hyperhomocysteinemia associated with arterial disease

progression

• Vitamin Intervention –stroke

prevention: cocktail of B6, B12, folic acid- 2 years, p=N/S Toole,

JAMA 291:565, 2004

• Heart Outcomes Prevention

Evaluation 2: folic acid,

B6,B12, 5 years, p=N/S, tx group had increased unstable

angina Lonn, 2006

• Post coronary stent

procedures given IV dose folic acid, B6, B12, 6 months,

higher restenosis Lange, NEJM

2673,2004

Vitamin D & CVDLichtenstein, J Lipid Research 50:S429, 2009

• Evidence for association:

• Higher incidence of CVD during winter months & in higher geographic latitudes of residence

• Low circulating 25 OH D associated with hypertension, Type II DM, metabolic syndrome

• Data from NHANES survey cohort, Health Professionals study,Framingham Offspring study

• RCT: Women’s Health Initiative-

calcium, vitamin D, placebo.

– CVD secondary outcome

– 7 years, p=N/S for coronary & cerebral risk reduction

Macular Degeneration

• Eye disease that damages the macula

• Macula allows for central vision & ability

to see details

• AMD gradually destroys this ability

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NEI’s Age-Related Eye Disease Study (AREDS) ARCH. OPHTHALMOL. 119:1417,2001

• 3,640 subjects with all stages of AMD

• 55-80 years old, average of 69 years

• Random assignment to 4 groups1. Antioxidants

2. Zinc and copper

3. Antioxidants, zinc, and copper

4. Placebo

• Results: Reduced risk of progression to Advanced AMD with the antioxidant, zinc, copper formula

• NO benefit w milder forms of AMD or cataract prevention

AREDS Formulation

Vitamin C 500 mg

Vitamin E 400 IU

Beta carotene 15 mg

Zinc (zinc oxide) 80 mg

Copper (cupric

oxide)

2mg

Current recommendations:

• “Supplement on individual basis”

• “Supplements not recommended for all

patients given recent information on

vitamin E and beta carotene”

• Concern for smokers & those with CVD

• Jager, Age Related Macular Degeneration, NEJM 358:2606, 2008

Immunosenescence:Immunosenescence:collective changes in immune collective changes in immune

function with agingfunction with aging

Antioxidant stores Antioxidant stores

become depleted become depleted

after numerous after numerous insults to the insults to the immune systemimmune system

Wintergerst, 2007

Altered Immune Activity

Increase Macrophage and NK derived Inflammation

Increased ROS Production

Increased T-cell Apoptosis

Micronutrients associated Micronutrients associated with Immune Responsewith Immune Response

Water Soluble VitaminsWater Soluble Vitamins Vitamin B6Vitamin B6

Vitamin CVitamin C

FolateFolate

Vitamin B12Vitamin B12

Fat Soluble VitaminsFat Soluble Vitamins Vitamin AVitamin A

Vitamin DVitamin D

Vitamin EVitamin E

MineralsMinerals SeleniumSelenium

CopperCopper

IronIron

ZincZinc

Wintergerst. 2007

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Elderly immunity: where are we with E?

• Healthy elderly, 4 months, E (all rac-αToco), given at doses 60,200,800 IU

• No adverse effects

• Later, in elderly nursing home residents, E at 200IU, p=.04 for lower respiratory infections

• Meydani, 1998, 2004

• Healthy elderly not duplicated:

• E- 200 mg, or multi-vitamin, 15 months. E

group increased illness duration, more fevers, more

symptoms (p=.03) Graat,

JAMA 288:715,2002

VITAMIN E: FLETCHER, FAIRFIELD, JAMA

287:(23),2002

• No changes in absorption with aging, * plasma increases seen with aging due to age-related changes in lipoprotein metabolism

• DOSES of 800IU+ ?? Risk

• ?? WILL SUPPLEMENTS OPTIMIZE NUTRITIONAL STATUS?

100%DV for 66% of nutrients

Supplement selection:

No evidence of greater stress reduction fromExtra C & Bvitamins

Less iron & vitaminK

No evidence that small doses are beneficial; studiesuse larger amts.

FDA requiresDisclaimer when“structure or Function claimMade”

US Pharmacopeia: 5 quality tests-contains label ingredients;-contains declared amounts;-dissolves easily;-screened for metals,pesticides;

-manufactured in sanitary,controlled conditions. OrNational Formulary (NF) on label Fulfills USP standards,but not FDAapproved, or USP accepted use

Men need 9mg iron or less;May add selenium (200mcg),Vitamin E, lycopene (15mg)

Won’t make one more Energetic!;

Very important: USP onLabel means product met:

SMART VITAMIN/MINERAL SUPPLEMENT SELECTION

• CHECK FOR USP DESIGNATION

• DO NOT EXCEED UPPER LEVEL ESTABLISHED FOR

• VITAMIN D: 100mcg or 4,000 IU : toxic

• VITAMIN A: 3,000 mcg of “preformed”

• B6: 100 mg

• FOLATE: 1,000 mcg

• FORGET THE “GIMMICKS” OF ADDED

ENERGY, OR SPECIAL INGREDIENTS

Optimizing nutritional status:

ALWAYS SELECT FOODS

FIRST! SHOULD NOT BE A

“CRUTCH” FOR POOR FOOD

SELECTIONS!!

AVOID MULTIPLE, SERPARATE

SELECTIONS UNLESS SPECIFICALLY

ADVISED BY YOUR PHYSICIAN

Guidelines:

Vitamin & mineral quantityGuidelines:

Dietary Reference Intakes(DRI) & *Upper Intake

Level (UL), Institute of MedicineFood, Nutrition Board

IOM: 202-334-2352 orwww.iom.edu or www.nap.edu

event

Report adverse event

FDA Medwatch:1-800-332-1088 or

www.fda.gov/medwatch/index.html

Reputable information

National Institute Health:(NIH) Office Dietary

Supplements: www.dietary-supplements.info.nih.gov

US Pharmacopeia:maintainsMonographs & safety informationwww.U.S.P.org

USDA: resource listingwww.nal.usda.gov/fnic

Consumer Lab: independent testingwww.consumerlab.com

Registered DietitianNational registry: ADA

www.eatright.org

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Final comments…

• Consensus E supplementation does not

provide CV benefit

• E supplementation MAY increase mortality

– HOPE TOO, ↑risk heart failure, p=.007

• Moratorium on E supplement prescriptions

• Data on non-healthy, as well as healthy

• Not targeted those with exaggerated oxidative stress

E and special populations: high oxidative

states

• Haptoglobin (Hp), antioxidant protein

• Two common genetic polymorphisms,

Hp2-2 genotype less capable anti-oxidant

protection

• DM state of marked oxidative stress. Hp2-

2DM have 2-5 fold increased CV events as contrasted to those w DM w Hp1or

Hp2-1

Milman, et al 2008 – see next slide for study details

E and special populations: high oxidative

states

E and special populations: high oxidative

states

• Vitamin E, 400IU daily, n= 1,434 Hp2-2,

DM, over age 55: significant reduction in cardiovascular death (p=.01)Milman, 208

• Several Vitamin E trials in hemodialysis

patients also demonstrated significant CV benefit from supplemental E, (50-800 IU),

(2 weeks to 2 years), Boaz,2000; Panzetta, 1995; Yukawa, 1995; Mune, 1999)