Calorie Restriction andCalorie Restriction andCalorie Restriction Mimetics:Calorie Restriction Mimetics:

WillWill ‘‘ModernModern’’ Medicine Rediscover BasicMedicine Rediscover BasicEvolutionary Perspectives on Human HealthEvolutionary Perspectives on Human HealthBefore ItBefore It’’s Too Late? Rethinking Our Losings Too Late? Rethinking Our LosingBattle Against the Diseases of AgingBattle Against the Diseases of Aging

Douglas F. Watt, Ph.D.

Cambridge City Hospital

Harvard Medical School

dfwatt@rcn.com

Dedication: Richard F. Watt (1917-2010)

Offered pithy comment (when Iwas too young to appreciate it):“Aging is vastly overrated, butmost of the time it beats thealternative.”

A gentleman and a scholar.

Passionate believer in the ideathat knowledge should be usedto benefit the greater good, andthat the deepest knowledgecould further the greatest socialgood. Advocate for thedisadvantaged and forgotten.

Recent epiphanies . . . Has Darwinbeen forgotten in modern medicine?

Recent discussion with cardiologist: Exceptional person and physician –discussing current lifestyles vs. hunter-gather (HG) lifestyle.

Didn’t believe that those issues immediately relevant to discussion of CVrisk and disease – unaware that CV disease didn’t exist in HGs.

Medical students taught nothing about nutrition or lifestyle in any kindevolutionary context – young MDs have no concept that modern humansare living in an alien environment from standpoint of genetic lineage.

Has modern medicine abandoned Darwin’s central insight? Isn’t evolution the keystone concept in the science of biology? Touchstone concept - the relatedness of all life, the conserved nature of

living processes, and critical nature of organism/environment interaction. Diseases of aging virtually don’t exist in HGs, even when younger ages of

HG mortality are corrected for. Has reliance on high technology replaced any evolutionary perspective on

diseases of aging? Missing the forest for all the trees? Nothing is harder to see than the blind spots of an entire culture. “You can’t expect someone to understand something if their salary

depends on their not understanding it.” Mark Twain

We are in an alien environment fromthe standpoint of our genome!!

Original Evolutionary Environment Modern Technological Environment1. Intense aerobic exercise (2+ hrs/d) 1) Minimal to no aerobic exercise2. 9+ hours sleep (see #1) 2) 7 hours or less of sleep (see #1)3. Calorie limitations (periodic CR) 3) Unlimited calories4. High phytochemical/polyphenol diets 4) Low phytochemical/polyphenol diets5. Omega-6/Omega-3 ratio 1:1 to 3:1) 5) Omega-6/Omega-3 ratio 12:1 - 20:16. High intake of fiber (~50-100 gm/d) 6) Low intake of fiber (≤ 15 gm/d)7. Low sugar/carbs, except from fruits 7) High sugar/carbs, not from fruits8. Intake of K+ > Na+ (K+ > 3 gm/d) 8) Intake of Na+ > K+ (Na+ > 3 gm/d)9. Pro-alkaline diet 9) Pro-acidic diet10. Minimal to no glycated proteins 10) Lots of glycated protein (milk products)11. Intimate social groups/tribes 11) Social isolation common12. Early mortality: infection, starvation, 12) Death from an advanced disease of

predation, and violence/wars: aging with life expectancy 75 to 82life expectancy 30 to 35

Although most discussions of the Paleolithic diet don’t mention calorie restriction(CR) as an intrinsic component, evidence argues that periodic CR and evenstarvation were common events that drove pre-agricultural humans into agricultureand out of a hunter-gatherer lifestyle. We have not looked back since, but we mayhave underestimated the costs of this huge cultural innovation (food technology).

Biomarkers . . . . Then and Now

Hunter Gatherers Current Technological Societies

1. BMI under 22 for most 1) ~30% BMI > 30, ~30% BMI 25-302. Total cholesterol under 125 2) Total cholesterol ~ 200 or higher3. Blood pressure 100-110/70-75 3) 120/80 (‘normative’), w/ HTN common4. VO2 max good to superior 4) VO2 max fair to poor (sedentary lifestyles)5. Homocysteine low (4-8 mmol) 5) Homocysteine MUCH higher (9-15 mmol)6. Vitamin D ~ (50-100 ng/ml) 6) Vitamin D deficiency common (20-40 ng/ml)7. High insulin sensitivity 7) Variable degrees of insulin resistance8. Physical activity > 1000 kcal/d 8) Physical activity ~ 150-490 kcal/d typical.9. Serum redox value high 9) Serum redox levels in other direction10. Cytokine ratios balanced 10) Cytokine ratios tipped > pro-inflammatory.

Is the US HealthcareSystem Headed For ACatastrophic Collapse?

The Approaching Tsunami

and Its Frightening Dimensions

Multifactorial Explosion of Costs

Aging Demographic is Only Part of the Problem:

Over-Reliance on High Technology

Frightening Statistics of Our LosingEffort Against the Diseases of Aging

America's health care bill now exceeds GDP of France ↑ @>7%/yr. TOTAL OUTLAY: 2.57 TRILLION in 2010, or $8370/person.

Total expenditures as % of GNP (2010): 17.4% (highest in world). U.S. health care spending is expected to increase at similar levels for

the next 10 yrs from 2.6 to $4.7 TRILLION in 2019 (~20% GNP). Health care spending accounts for 10.9% of GDP in Switzerland,

10.7% in Germany, 9.7% in Canada and 9.5% in France despite allthese countries providing universal health care.

Health insurance expenses fastest growing cost for employers. Healthinsurance costs overtake TOTAL PROFITS by late 2008.

Health outcomes on composite of critical measures trail virtually everyother industrialized society. In last 20 yrs, life expectancy has droppedfrom 11th to 38th place. Infant mortality rate of 6.37/1000 is 42nd out of221 countries (> all of Western Europe.)

~ 75-85% of America’s healthcare dollars spent on treatment forestablished illness, < 5% spent on prevention (Walter Bortz, MD).

Why (and how) are we getting such poor results for so much $?

Cost Of Health Care in 2030:$16,000,000,000,000 if current trends cont.

The Explosion Of ObesityIn The United States

Promoting a ‘Tsunami’ of Age-Related Illness:

A Risk Factor For Many Diseases Of Aging

Pro-Inflammatory – Apipose Tissue

Alters Endocrine Milieu for Body

Approximately one-third of the adult population nowis obese and an additional third is overweight. 2.2billion obese people worldwide!!

Obesity in 2009 in USA

Stress and ChangingConcepts of Inflammation

Stress and Inflammation Intrinsically Linked

Inflammation Causes ‘Collateral Damage’

Aging Probably Upregulates Inflammation

Inflammation Implicated in All Diseases of Aging

Modern Life is Highly Pro-Inflammatory

Modern Life Promotes Aging?

Why is stress such an important risk factor indiseases of aging? Socioeconomic status large variable in health, indexing,

among other things, high baseline stress levels.

Stress destabilizes sleep, promotes substance abuse,depression & many other psychiatric conditions.

Stress traditionally seen as a psychological/psychiatric issue,having little to do with body physiology (manifestly untrue).

Stress → changes in fundamental cellular pathways involved in metabolism (particularly of fats), inflammatory responses,and immune and endocrine function (next slide).

Stress probably co-evolved w/ inflammatory/immuneresponses, both jointly recruited by classic activators ofpredatory attack/injury, social isolation, and infection.

Stress creates inflammation, immune challenges activate orexacerbate classic HPA axis stress responses.

Nature created a seamless integration of these systems (nocompartments!), and our science has to model this better.

Stress, Catecholamines,Lipids and Inflammation

Catecholamines are important inducers of cytokines,especially in macrophages (both α and β receptors).

Elevated cholesterol increases NE β receptor expression. Oxidized cholesterol (LDL) → increased cytokine production

from macrophages, suggesting linkages between oxidativestress and promotion of inflammation.

Complements how INFLAM → OS (synergistic relations) Activating the SNS, and promoting HTN both have pro-

inflammatory effects (both ↑ IL-6). Beta blockers reduce expression of both IL-6 & CRP. Vascular smooth muscle cells release IL-6 if exposed to

angiotensin-II (suggesting HTN → inflammation loops). Hypertension also inhibits factors that inhibit clotting (pro-

clotting and therefore promoting thrombus formation). These considerations suggesting many looping control

mechanisms in the promotion of vascular disease.

Systemic Effects of Inflammation

INFLAM & Oxidative Stress LinkedHow much ‘collateral damage’ does inflammation producein the context of aging? No one truly knows . . . .

Aging Promotes Inflammation

Aging associated w/ decline in adaptive immunity, andcompensatory upregulation of innate immunity.

Decreasing ‘naïve’ T cells, due to life long exposure topathogens, esp. chronic background exposure to viruses.

Accumulation of memory T and effector (CD8+CD28) cells→ increased pro-inflammatory cytokines

Activation of macrophages/glial cells in body/brain.

Imbalance of inflammatory/anti-inflammatory networks.

In toto, this results in a low-grade systemic chronic pro-inflammatory status (“inflamm-aging”).

Increased pro-inflammatory cytokines primary marker, alongwith other immune system shifts (eg coag cascade)

What Restrains Inflamm-aging?

Genes (e.g., IL-10 polymorphism shows very reduced AD) butprobably many other unknown SNPs.

Exercise (aerobic).

Diet (multiple factors and issues).

Fiber (more than just protecting GI system) – sets inflammatoryparameters.

Omega 3/Omega 6 ratio ~1:2 to 1:4.

Numerous polyphenols (virtually all reduce NF-kB, a primarytranscription factor in inflammation).

Curcuminoids most highly regarded anti-inflammatory polyphenol.

Resveratrol and EGCG also, and many others.

Sleep vs sleep deprivation.

No severe sustained stress, social comfort, (possibly) play.

Effects of these individual factors synergistic in either direction?