THE ANTI-AGING THE ANTI-AGING TRIAD: TRIAD:

STEPHEN HOLT, MD, ChB., DSc, LLD (Hon.), PhD, ND, FRCP(C) MRCP (UK), FACP, FACG, FACN, FACAM,

OSJ, Distinguished Professor of Medicine, (Scientific Advisor to Natural Clinician, LLC)

•CALORIE RESTRICTION AND MIMETIC COMPOUNDS

•SUPORTING TELOMERES AND TELOMERASE

•STEM CELL TREATMENTS

THE MOST IMPORTANT AREAS THE MOST IMPORTANT AREAS OF SCIENCE IN LONGEVITY OF SCIENCE IN LONGEVITY

PROMOTIONPROMOTION• There are three innovative areas of medical science that

will drive therapeutic and research interest in the first quarter of this millennium.

• These three areas constitute “The Anti-Aging Trilogy”:

1. The use of calorie restriction or calorie restriction mimetic compounds

2. The application of techniques to lengthen telomeres and modulate telomerase activity

3. The use stem cell treatments.

APPLYING CALORIE APPLYING CALORIE RESTRICTIONRESTRICTION

• A large body of medical evidence shows that restricting calories of the order of 30-50% below average free feeding calorie intake inhibits aging processes in all species tested.

• A target of about 40% reduction in average calorie intake (2,000 kCal/day) is required, but compliance may be unattainable.

• Calorie reduction must occur with nutrient dense foods. The Roy Walford concept of the high/low diet (The 120 Year Diet).

A PIVOTAL PUBLICATION, WALFORD 1986: A PIVOTAL PUBLICATION, WALFORD 1986: HIGH/LOW DIET WITH THE CONCEPT OF HIGH/LOW DIET WITH THE CONCEPT OF

“UNDERNUTRITION WITHOUT MALNUTRITION”“UNDERNUTRITION WITHOUT MALNUTRITION”

OUTCOMES OF CALORIE OUTCOMES OF CALORIE RESTRICTIONRESTRICTION

• Favorable effects on CVS: reductions in heart rate, blood pressure, LDL cholesterol and triglycerides (Amelioration of Metabolic Syndrome X).

• Promotion of insulin sensitivity with improvements in glucose tolerance (normalization blood glucose).

• Increase in protein synthesis with enhanced elimination of abnormal proteins

• Modulation of apoptosis with DNA support.• Reduction of oxidative stress.

OUTCOMES OF CALORIE OUTCOMES OF CALORIE RESTRICTIONRESTRICTION

• Reduction in body temperature.

• Reduction in fat mass, including visceral adiposity, with increase in muscle mass.

• Restoration of hormonal secretions that tend to fall with age, e.g. DHEA and HGH.

• Enhanced cognitive function and mood.

• Improved ability for physical activity.

• Stimulation of growth factors eg BDNF

SUMMARIZING BIOPHYSIOLOGICAL SUMMARIZING BIOPHYSIOLOGICAL EFFECTS OF CALORIE RESTRICTION EFFECTS OF CALORIE RESTRICTION

• Altered enzyme expression in protein metabolism and synthesis

• Apoptosis regulation

• Modification of actions of chaperone molecules

• Reduction in glycosylation

• Reversal of dysglycemia

SUMMARIZING BIOPHYSIOLOGICAL SUMMARIZING BIOPHYSIOLOGICAL EFFECTS OF CALORIE RESTRICTION EFFECTS OF CALORIE RESTRICTION

• Suppression of inflammatory responses

• Hormetic effects• Inhibition of glycolysis with insulin

sensitizing actions• Genetic regulation e.g. Sir2 or

human homologous SIRT1g

FOR THE SKEPTICFOR THE SKEPTIC

Source: Reproduced from Life Extension Magazine

CONCEPTS OF CALORIE CONCEPTS OF CALORIE RESTRICTION MIMETICS (CRM)RESTRICTION MIMETICS (CRM)

• A CRM is an agent that has the ability to reproduce one or more of the principal biological effects of calorie restriction (Weindruch, R, et al. J.Geront, 56, 20-33 2001).

• Many CRM of pharmaceutical or natural origin induce substantially similar bio-physiological changes that are documented with prolonged dietary calorie restriction, in many species.

CRM IN ANTI-AGING THERAPEUTICSCRM IN ANTI-AGING THERAPEUTICS• Synergistic combinations of natural substances

with Calorie Restriction Mimetic properties have been identified and combined for a nutritional approach to longevity.

• Examples of CRM: Metformin, Resveratrol, Carnosine, Gymnema, Alpha Lipoic Acid, Cinnamon, Avocado, OPCs (grape seed), Ellagic Acid, N-Acetyl-Carnitine, Green Tea

•

A NATURAL CRM SUPPLEMENT DEVELOPED A NATURAL CRM SUPPLEMENT DEVELOPED BY HOLT MD LABS FOR NATURAL CLINICIANBY HOLT MD LABS FOR NATURAL CLINICIAN

THE POWER OF SYNERGY

A PROTOCOL FOR NUTRITION A PROTOCOL FOR NUTRITION AND LONGEVITYAND LONGEVITY

• Calorie restriction of a tolerable degree combined with natural calorie restriction mimetics.

• Maintenance of nutrient density by the use of mixed fruit, vegetable and greens powders containing minerals and full RDI of vitamins

• Extra mineral enrichment• Obsessional detection and treatment of

Syndrome X (70 million Americans)

THE SYNDROME X BRIGADETHE SYNDROME X BRIGADE

TELOMERES AND TELOMERASETELOMERES AND TELOMERASE•Telomeres are DNA caps at the end of chromosomes that function to prevent aberration or loss of genetic information during cell division.

•The enzyme telomerase acts to extend telomeres and reduce their shortening which occurs with repeated cell division.

•Telomere length correlates with age and short telomeres result in cell senescence, and abnormal chromosome function.

•Shortened telomeres interfere with the normal function of genes, propagate cancer, cause abnormal immune function, promote chronic disease and they are believed to be a direct cause of aging in tissues.

TELOMERES TELOMERES

Source: Reproduced from www.spectracell.com

TELOMERES AND TELOMERASETELOMERES AND TELOMERASE

•Telomerase activity is found preferentially in cancer, germ cells and stem cells.

•The idea of lengthening telomeres is an attractive anti-aging intervention.

•Lengthening telomeres by inducing telomerase presents some hypothetical risks of promoting cancer.

•Suppressing telomerase is proposed as a cancer treatment.

SAFE TELOMERE SUPPORT OR LENGTHENINGSAFE TELOMERE SUPPORT OR LENGTHENING

• Many factors alter telomere length e.g. age, sedentary lifestyles, chronic inflammation, oxidative stress, hormonal deficiencies and abnormal glucose metabolism.

• Single agents that may increase the activity of telomerase have been proposed for use as dietary supplements to support telomere length (Astragalus) but safety issues exist.

SAFE TELOMERE SUPPORT OR LENGTHENING: SAFE TELOMERE SUPPORT OR LENGTHENING: THE TELOMERE SUPPORT PROTOCOLTHE TELOMERE SUPPORT PROTOCOL

• Initial telomere testing• Positive lifestyle change• Dietary adjustments• Meticulous disease management e.g. Syndrome X

and Diabetes mellitus• Miscellaneous interventions: reduction of

cardiovascular risk factors, control of inflammation, exercise programs, hormone supplementation

• Nutrient, botanical and herbal supplements

NUTRACEUTICAL INTERVENTION FOR NUTRACEUTICAL INTERVENTION FOR TELOMERE LENGTHENINGTELOMERE LENGTHENING

• Synergistic safe combinations of the following agents is optimal: Chinese Ginger Root, Gingko biloba, N-Acetyl-L-Cystine, vitamins B12, D3, E, Nicotinamide, and Folic acid

• Peer-review medical literature supports the above nutrient composition and the use of omega 3 fatty acids from enteric coated fish oil.

• Extracts of Astragalus that directly induce telomerase activity to lengthen telomeres cannot be considered to be safe.

Many Stem Cell TypesMany Stem Cell TypesReproduced from SA Biosciences, Pathways, 2009Reproduced from SA Biosciences, Pathways, 2009

Stem Cell Therapies: Stem Cell Therapies: Disadvantages and LimitationsDisadvantages and Limitations

• Embryonic Stem Cells, Embryonic Germ Cells and Fetal Tissue Stem Cells pose major ethical and moral problems which cannot be resolved.

• Cord Blood and Placental Stem Cells pose unresolved technical problems, e.g. survival.

• Adult Stem Cells remain an imperfect therapeutic procedure, except bone marrow.

• Induced Pluripotent Stem Cells (Yamanaka, 2006) hold promise

Adult Stem CellsAdult Stem Cells• Adult Stem Cells (ASC) live in niches in

most organs and they can migrate. • They are tethered in niches by adhesion

molecules that determine cell migration and niche retention. Compounds that interfere with adhesion factors may mobilize ASC.

• Most information is known about Human Bone Marrow Adult Stem Cells.

A Novel and New Stem Cell Strategy in A Novel and New Stem Cell Strategy in Integrative Medicine Practice: Induced Integrative Medicine Practice: Induced

Adult Stem Cell Recruitment (IASCR)Adult Stem Cell Recruitment (IASCR)

• Induced Adult Stem Cell technologies involve the stimulation of endogenous stem cells to regenerate or heal diseased or ailing tissues.

• Many compounds of natural or pharmaceutical origin may play an active role in the proliferation of human Adult Stem Cells or cells carrying markers CD34+ and CD133+ (Jensen GS et al, 2002 and Bickford P et al, 2006, Holt S, 2008).

The Concepts of IASCR: Part 1 The Concepts of IASCR: Part 1 • Mobilize Adult Stem Cells from bone

marrow and other niche locations (?)• Increase circulation of ASC with a

semicontinuous, safe stimulus. Herbs, botanicals and nutrients are preferred to drug approaches (cost, side effects)

• Protect stem cells from oxidative damage• Encourage homing to desired target organ

The Concepts of IASCR: Part 2 The Concepts of IASCR: Part 2

• Assistance in the differentiation of Adult Stem Cells to replace cell types of the diseased organ has to be developed.

• A body of research demonstrates that human bone marrow Adult Stem Cells are able to “home in” on diseased organs and differentiate into many cell types (Egletis, 1997 and Korbling et al, 2002).

Factors that Mobilize Stem or Factors that Mobilize Stem or Progenitor CellsProgenitor Cells

• DRUGS (or isolated biologicals in clinical use or trials): IL1, IL3, IL6, Stem Cell Factor (s), erythropoetin, G-CSF etc.

• NUTRACEUTICALS : oleic acid, linolenic acid, blueberry, blue-green algae (AFA), green tea, fucoidan and vitamin D3. Putative releasers or antioxidant protection with fucoxanthin, beet root, spirulina, spinach, ashwagandha, grape seed extract. Cofactors Vit B12, Folate

In Vivo Release of ASC In Vivo Release of ASC (Data from Stemtech Inc. on AFA) (Data from Stemtech Inc. on AFA)

AFA increases CD34+ Stem Cells cf placebo

THE ANTI-AGING TRILOGYTHE ANTI-AGING TRILOGYStephen Holt MD, 2010Stephen Holt MD, 2010

CALORIE RESTRICTION

TELOMERES

STEM CELLS

CONCLUSIONS: THE ANTI-AGING TRILOGYCONCLUSIONS: THE ANTI-AGING TRILOGY

• Research and the application of technology to achieve the favorable outcome of calorie restriction, telomere support and stem cell treatments is proceeding at a rapid pace. Natural approaches exist.

• The Naturopath has a variety of botanicals, herbs and nutrients that have an evidence base to support:

1. Bio-physiological changes that occur with calorie restriction. “Calorie Restriction Mimetics”

2. Telomere support “Clinical Telomere Support”

3. Stem cell mobilization and potential recruitment