LIVING HIGH AND HEALTHY - Getting Stronger · 2016. 8. 21. · • Weight (BMI) and blood pressure...

Todd Becker

Ancestral Health Symposium

Boulder, Colorado

August 12, 2016

LIVINGHIGHANDHEALTHY

WhyColoradansandotherswholiveathighal>tudelivelonger,

andwhatflatlanderscanlearnfromthem

COPYRIGHT TODD BECKER 2016

QUESTIONS

Why is it that Boulder has very low rates of obesity, diabetes, cardiovascular disease and other causes of shortened lifespan? Is there a “Fountain of Youth” process that protects Boulderites? Can flatlanders tap into Boulder’s secret to extend healthspan?


WHY IS OBESITY SO LOW IN BOULDER?


Factor Boulder, Colorado

Cabell County, West Virginia

Obesity rate 12.4% 39.5% Climate Mountainous,

Sunny 300+days Flat, urban

Diet “Farm-to-table” food

Standard American Diet

Education (college grad)

>58%

25%

Income $67,403 $37,238

!Holt, Steve, “Has Boulder Figured Out the Obesity Problem?” TakePart, April 23, 2014, http://www.takepart.com/article/2014/04/23/boulder-low-obesity-rates!!

NO SINGLE CAUSE EXPLAINS OBESITY AND IT IS DIFFICULT TO SEPARATE CAUSE & EFFECT


Factor Possible Effectors (+/-) Diet Calories

Carbs (total/refined) Fats (saturated, omega-6) Fructose Anti-nutrients Pro-inflammatory factors Fiber/prebiotic deficiency Flavor / food reward

Exercise Calories Cardio Resistance Intensity and frequency

Genetics & epigenetics Ethnicity Ob genes

Psycho-Social Chronic stress Socio-economic status Access to transportation

A PROTECTIVE FACTOR?


•  It is difficult to identify any single driver of the modern surge in obesity, diabetes and metabolic syndrome?

•  It is hard to design interventional studies to show strong, sustainable improvements in humans

•  What if we could look for “natural experiments” that provide evidence of factors that protect against obesity and diabetes?

•  One way to do this: Look at geographic distributions

Less “transient” & more reliable than data from diet or exercise surveys & interventions

OBESITY AND DIABETES ARE ON THE RISE, BUT THE GEOGRAPHIC DISTRIBUTION IS UNEVEN


“Maps of Trends in Diagnosed Diabetes and Obesity”, Centers for Disease Control https://www.cdc.gov/diabetes/statistics/slides/maps_diabetesobesity_trends.pdf!


THE DECADAL INCREASES ARE STRIKING BUT UNEVEN ACROSS THE STATES



COLORADO AND A FEW OTHER STATES ARE BUCKING THE TREND…BUT WHY?


VIEWING OBESITY BY COUNTY SHARPENS THE PICTURE

Price, Anne and Ariel Godwin, “Mapping Transportation and Health in the United States”. Planetizen, Jan. 16, 2012, http://www.planetizen.com/node/53728 !COPYRIGHT TODD BECKER 2016

Price, Anne and Ariel Godwin, “Mapping Transportation and Health in the United States”. Planetizen, Jan. 16, 2012, http://www.planetizen.com/node/53728 !COPYRIGHT TODD BECKER 2016

AS DOES A COUNTY-BY-COUNTY VIEW OF DIABETES

COULD IT BE ACCESS TO TRANSIT ( ~HEALTHY FOOD) ?

Beth Mazur, “Obesity and food deserts”, Weight Maven, Jan. 2, 2012., https://weightmaven.org/2011/01/02/obesity-and-food-deserts/ !


…OR BEING PHYSICALLY ACTIVE?

!!“Healthcare: Obesity in America”, The Centrist Party, http://uscentrist.org/news/2011/healthcare-obesity-in-america, 2011!COPYRIGHT TODD BECKER 2016

Suggestive….!…but how reliable and objective are these estimates of “inactivity”?!

A SURPRISINGLY OVERLOOKED VARIABLE IS THE CLOSE MATCH BETWEEN OBESITY PREVALENCE AND ALTITUDE


Notice the large contiguous low obesity zone of the alpine and high plains Western U.S.!!But also the strikingly anomalous “low obesity Appalachian island” surrounded by the Southeastern “sea of obesity”!

Obesity Altitude

LONGEVITY TRACKS ALTITUDE IN EUROPE


Longevity Altitude

European Environment Agency, http://www.eea.europa.eu/soer/synthesis/synthesis/chapter5.xhtml

•  Representative sample of 422,603 adults across U.S.

•  Controlled for effects of age, sex, race/ethnicity, education, employment, temperature, diet, physical activity, and smoking

Results

•  Odds of obesity at sea level 4-5 times higher than at > 10,000 ft !!

OBESITY DROPS SHARPLY AT HIGH ALTITUDES

Study design Obesity vs. Altitude

Voss, J.D. et al., “Association of elevation, urbanization and ambient temperature with obesity prevalence in the United States”, International Journal of Obesity (2013) 37, 1407-1412


Boulder

•  617 Tibetan men and women, 30-70 yr

•  Shared genetics, diet, culture, economy

•  Living at 1200, 2900 and 3700 m

•  Analyzed BMI, waist circumference, etc.

•  Calorie consumption and physical activity estimated from questionnaires

Comment “The mechanism for these differences are not known, and we were not able to explain this by lower energy intake or increased physical activity. It is likely that the physical conditions such as low temperatures and low oxygen levels have a direct catabolic effect.”

OBESITY AND ALTITUDE: TIBET STUDY Study design

Lhamo Y. Sherpa et al., “Obesity in Tibetans Aged 30–70 Living at Different Altitudes under the North and South Faces of Mt. Everest “, Int J Environ Res Public Health. 2010 Apr; 7(4): 1670–1680.


Altitude Obesity

rate meters feet

1200 3900 19.7%

2900 9500 11.8%

3700 12,100 9.7%

Metric

Change per kilometer

BMI -1.43 kg/m2

Calorie Intake +1466 kcal

Physical activity +1984 METs

WHAT MIGHT LINK ALTITUDE TO OBESITY?

Factor Pro Con

Exercise Effort walking up and down slopes

Flat areas at high altitude (Utah)

Ethnicity Rural – urban ethnic differences

Tibet study – uniform ethnicity

UV Radiation Hormetic stimulus Vitamin D synthesis

Inconsistent

Air quality Cleaner alpine air Inconsistent Oxygen concentration

Hypoxia increases with altitude


•  VO2 max •  Mitochondria •  Insulin sensitivity •  Glucose transporters (GLUT4) •  Glycolytic enzyme activity •  Blood vessel growth •  Peripheral vasodilation •  Blood platelets, hemoglobin •  Erythropoietin

•  Obesity / body weight

•  Diabetes

•  Arterial blood pressure

•  Cardiovascular disease

•  Dementia

HYPOXIA CONFERS NUMEROUS BENEFITS

DECREASES (-) INCREASES (+)


Urdampilleta, Aritz et al., “Usefulness of intermittent hypoxia and exercise in obesity”, J Physiol Biochem DOI 10.1007/s13105-011-0115-1

HIGH ALTITUDE HYPOXIA CAUSES SUSTAINED WEIGHT LOSS IN HUMANS


•  Food intake spontaneously decreased -- even more so after return to low altitude

•  Basal metabolic rate significantly increased -- during and after the mountain stay

•  Weight (BMI) and blood pressure decreased -- at high altitude and 4 weeks after

•  Leptin plasma levels increased -- after 1 week, “despite reduction in body weight”; and eventually returned to baseline after 4 weeks at low altitude

Lippl, Florian J. et al. “Hypobaric Hypoxia Causes Body Weight Reduction in Obese Subjects”, Obesity (2010) 18, 675–681. doi:10.1038/oby.2009.509

•  20 obese male subjects, age 55.7 ± 4.1 years,

BMI 33.7 ± 1.0 kg/m2, indices of metabolic syndrome

•  Monitored before and after 1 week stay near Zugspitze, at 2650m (8694 ft), and for 4 weeks after return to low altitude

Zugspitze, Germany

HYPOXIA EXTENDS LIFESPAN AND REDUCES HEART DISEASE


Study

•  CU Denver School of Medicine & Harvard School of Global Health

•  Comprehensive study of death certificates from every county in U.S.

•  People living above 1500 m (4900 ft) vs. those near sea level

Results

♂  Men: lifespan increased 1.2-3.6 years

♀  Women: lifespan increased 0.5-2.5 years

•  Reduced ischemic heart disease

•  Increased COPD (more about this later)

M. Ezzati et al., “Altitude, life expectancy and mortality from ischaemic heart disease, stroke, COPD and cancers: national population-based analysis of US counties. J. Epidemiology & Community Health, 2012

HYPOXIA “TRAINING” FOR ATHLETIC PERFORMANCE


Intermittent hypoxic training (IHT) impact on sea-level performance Two training protocols: •  A: Living high, training low •  B: Living low, training high

Results •  Protocol A produced increases in endurance measures:

!  Running speeds !  Power output !  Oxygen flux

•  Protocol B had the opposite effect – decreases in all measures

•  Casts doubts on brief training with “hypoxic masks”

•  Meta-analysis of 11 studies found benefits training at 2500-3000m for at least 9.5 hours daily for at least 2 weeks

Benjamin D. Levine, “Intermittent Hypoxic Training: Fact and Fancy”, High Altitude Medicine & Biology, 6 July 2004, 3 (2); 177-193.

High = 2500m (8100 ft) Low = sea level

!  Erythropoietin !  Red cell mass !  VO2 max

BUT WHAT ARE THE MECHANISMS BY WHICH HYPOXIA REDUCES OBESITY?


Multiple proposed mechanisms:

•  Hormone signaling: Leptin and insulin

•  Hormetic sensing: PGC-1α / FNDC5 / BDNF

•  Anti-aging pathway: REDD1 protein, mTOR inhibition

HYPOXIA INCREASES LEPTIN SIGNALING


Rats treated with intermittent hypoxia (IH)

IH protocol:

•  IH: Alternating (120-s normoxia, 80-s total hypoxia) -- for 8 h

•  Control: normoxia for 8 h

Results:

•  6-fold increase in circulating leptin levels

•  Maked increase in immunoreactivity (sensitivity) of oxygen-sensing carotid body glomus cells that express Ob-Rb leptin receptors

Messenger, S.A., and Cinello, J. “Effects of intermittent hypoxia on leptin signaling in the carotid body”, Neuroscience 232:216-225 (March 1, 2013)

HYPOXIA INCREASES NEUROGENESIS


Intermittent hypoxia (IH) protocol:

•  Sprague Dawley rats •  Barometric pressure reduced to 84 mm HG, equivalent of 5000 m,

4 hours daily for 2 weeks •  BDNF levels measured with anti-BDNF antibody •  Screened for “anti-depressant like effect” using behavioral tests like

forced swimming and novelty-suppressed activity

Results:

•  IH produced anti-depressant effect, according to behavioral scores

•  IH enhanced BDNF and cell proliferation in hippocampus

Zhu, Xin-Hong et al., “Intermittent Hypoxia Promotes Hippocampal Neurogenesis and Proucdes Antidepressant-Like Effects in Adult Rats”, J. Neuroscience, 22 September 2010, 30 (30: 12653-12663.

HYPOXIA SUPRESSES mTOR ACTIVITY


What is mTOR? (Mammalian target of rapamycin)

•  Master regulator of protein synthesis and growth processes

•  Associated with aging and degenerative diseases

•  Barometric pressure reduced to 84 mm HG, equivalent of 5000 m, 4 hours daily for 2 weeks

Findings:

•  Hypoxia up-regulates the stress-induced protein REDD1

•  REDD1 represses mTORC1 activity

•  Repressing mTOR conserves energy by limiting protein synthesis

Dourangsone D. Vadysinsak and Leif W. Ellisen, “mTOR under hypoxia”, Methods Mol. Biol.2012: 821: 45-58. doi: 10.1007/978-1-61779-430-8_4

HYPOXIA ACTIVATES A POWERFUL “STRESS SENSOR” THAT TRIGGERS A WIDE-RANGING METABOLIC CASCADE

Hypoxia

PGC-1-α* : PPAR-γ


FNDC5/irisin

BDNF : TrkB

Appe$tesuppression

Exercisesalience

InsulinSensi$vity

FNDC5/irisin

WAT!BAT!

mitochondrial!biosynthesis!

Thermogenesis Inflamma$on

master!regulator!

PGC-1-α / FDNC5 / BDNF pathway

Autophagy

leptin REDD1

mTOR

*Peroxisome proliferator-activated gamma coactivator 1-alpha

BDNF (Brain-Derived Neurotrophic Factor)


Central metabolism (Brain and CNS) •  Stimulated by irisin from exercise, cold, hypoxia

•  Produced in hippocampus and hypothalamus •  Promotes neurogenesis

•  Suppresses appetite, increases metabolic rate (REE)

•  Low BDNF is associated with obesity

Peripheral metabolism •  Despite it’s name, BDNF is also produced in muscle, fat

and liver

•  Interacts with modulators of energy and appetite: insulin, leptin, cortisol

•  Inversely correlated with blood glucose levels •  Increases thermogenesis, UCP-1

•  Improves insulin sensitivity

Emily E. Noble et al., “The lighter side of BDNF”, Am. J. Physiol Regul Integr Comp Physiol. 2011 May, 300 (5): R10530R0169, doi: 10.1152/ajpregu.00776.2010

BDNF : TrkB

BDNF BDNF

BDNF

PGC-1α CASCADE ALSO SPURS AUTOPHAGY


•  Damaged proteins sequestered in autophagosomes

•  Autophagosomes fuse with lysosomes

•  Contents are digested

•  Enhances cellular “fitness”, reduces frequency of apoptosis

•  Extends longevity in animals

Madeo, Frank et al., “Can autophagy promote longevity?” Nature Cell Biology 12 (9) Sept. 2010: 842-846

HOW AUTOPHAGY PROMOTES LONGEVITY


REDUCES INCREASES

Misfolded, aggregated proteins Innate immune response

Inflammation Removal of intracellular pathogens

Apoptosis and necrosis (cell death)

Senescence (cell aging)

Oncogenesis (cancer genes)

Madeo, Frank et al., “Can autophagy promote longevity?” Nature Cell Biology 12 (9) Sept. 2010: 842-846

SO… DO WE NEED TO MOVE TO THE MOUNTAINS OR WEAR HYPOXIA MASKS TO LOSE WEIGHT & LIVE LONGER?


THREE THEORIES OF AGING


For more on this, read “Spring Chicken” by Bill Gifford, and see my related post, “Live Longer!” on gettingstronger.org

Genetic Program

Damage Accumulation

Hyperfunction

Advocates Jay Olshansky Aubrey DeGrey Suzanne Somers

Denham Harman Mikhail Blagosklonny Valter Longo Ron Rosedale

Drivers of aging

Fixed program Maximum lifespan Telomeres

Free radicals (ROS) DNA damage

Overactive cellular processes: mTOR, inflammation, cell division, lipogenesis

How to live longer

“Hack” program with hormones, supplements and telomerase

Take antioxidants Avoid: toxins, UV, cell phones

Hormesis, especially after middle age: calorie restriction, exercise, cold, hypoxia, bitter herbs

Problems for the theory

Hormones & telomerase actually increase cancer

Antioxidants impair “oxidative” cellular signaling & repair; Naked mole rat

Limited evidence in humans

AGAINST THE ACCUMULATED DAMAGE THEORY


•  Naked mole rats live in dark underground burrows

•  In captivity, they are exposed to much higher oxidation than in the wild

•  Their proteins show much higher levels of oxidative damage than with normal lab mice

•  Yet they show up-regulation of endogenous antioxidant protection

Normal lab mice live 3 years Naked mole rats live 30+ years!

HORMESIS

•  Hormesis is a set of defense, repair and adaptation mechanisms

•  The result is supercompensation and increased resilience to stressors

•  Hormesis is an optimum, best approached gradually.

•  Excess stress is harmful!


The beneficial response of an organism to a low dose stressor that is otherwise detrimental or lethal at high doses

THERE ARE FOUR TYPES OF HORMESIS


Structural hormesis

Defense hormesis

Metabolic hormesis

Psychological hormesis

Weight lifting Allergen immunotherapy

Calorie restriction Appetite deconditioning

Barefoot running Polyphenols (curcumin, green teas, caffeine)

Exercise Exposure therapy (phobias, anxiety)

Tanning (melanogenesis)

Cold exposure Sleep restriction therapy

Incremental retinal defocus

Hypoxia

METABOLIC HORMESIS IS A RESPONSE TO EXTERNAL AND INTERNAL ENERGY DEMANDS

Hypoxia

PGC-1-α : PPAR-γ


FNDC5/irisin

BDNF : TrkB

Exercise Cold

Appe$tesuppression

Exercisesalience

InsulinSensi$vity

FNDC5/irisin

WAT!BAT!

mitochondrial!biosynthesis!

Thermogenesis Inflamma$on

master!regulator!

PGC-1-α / FDNC5 / BDNF pathway

Autophagy

Calorie Restriction

leptin REDD1

mTOR

PGC-1α SENSES NOT JUST HYPOXIA, BUT COLD STRESS AND ENERGY STATUS

Fernandez-Marcos, Pablo J, and Johan Auwerx. “Regulation of PGC-1α, a Nodal Regulator of Mitochondrial Biogenesis.” The American Journal of Clinical Nutrition 93.4 (2011): 884S–890S. PMC. Web. 24 July 2016.

Figure 1. A metabolic sensor network regulating energy expenditure

HORMETIC ACTIVATION OF THE PGC-1α CASCADE MAY COMBAT OBESITY MAKING US WANT TO EXERCISE


•  Hormesis moderates appetite, but what about the other side of the equation – the urge to exercise?

•  Hormetic activation of PCG-1α cascade promotes exercise salience by ramping up mitochondrial function, metabolic rate, and thermogenesis allowing the rapid release of energy on demand.

•  Conversely, Inflammation impairs mitochondrial function and energy release.

•  Yet hormesis also activates anti-oxidant systems like Nrf-2 that protect against this inflammation.

•  Hence, both the vigorous hormetic lifestyle and the sedentary inflammatory lifestyle tend to be self-reinforcing

Alistair V. Nunn et al., “Inflammatory modulation of exercise salience: using hormesis to return to a healthy lifestyle” Nutrition & Metabolism 2010, 7:87. http://www.nutritionandmetabolism.com/content/7/1/87

VIRTUOUS CYCLE OF HORMESIS


Hormesis

Mitochondria

Energy

Inflammation

Exercise Eating

Exercise Cold/hot Calorie restriction Polyphenols

Sedentary life Comfort Caloric excess Inflammatory foods

VICIOUS CYCLE OF INFLAMMATION


Hormesis

Mitochondria

Energy

Inflammation

Exercise Eating

Exercise Cold/hot Calorie restriction Polyphenols

Sedentary life Comfort Caloric excess Inflammatory foods

DOES A “HORMESIS SHORTAGE” EXPLAIN OUR CRISIS OF OBESITY AND METABOLIC SYNDROME?


“Ancient man was a hunter-gatherer, often travelling long distances to find food, avoid threats and seek shelter. In contrast many modern western societies have transformed their surroundings in order to minimise (or even eliminate) environmental threats and stresses that our ancestors were exposed to, including food and water shortages, predation, infections, extremes of temperature and the need to carry out regular physical activity.”

“The result is a vicious cycle that increases oxidative stress and reduces metabolic flexibility and perpetuates the disease state. In contrast, hormetic stimuli can induce an anti-inflammatory phenotype, thereby enhancing exercise salience, leading to greater biological fitness and improved functional longevity.”

Alistair V. Nunn et al., “Inflammatory modulation of exercise salience: using hormesis to return to a healthy lifestyle” Nutrition & Metabolism 2010, 7:87. http://www.nutritionandmetabolism.com/content/7/1/87

SO….ACTIVATE YOUR INNER BOULDERITE!

You don’t need to live a mile high to stimulate your natural stress response

Push yourself to tolerate discomfort and even enjoy it

Start gradually and build up your tolerance

Take cold showers

Hike and li2 heavy things

Eat less frequently


REFERENCES Altitude, obesity and health 1.  Holt, Steve, “Has Boulder Figured Out the Obesity Problem?” TakePart, April 23, 2014,

http://www.takepart.com/article/2014/04/23/boulder-low-obesity-rates!

2.  “Maps of Trends in Diagnosed Diabetes and Obesity”, Centers for Disease Control https://www.cdc.gov/diabetes/statistics/slides/maps_diabetesobesity_trnds.pdf!

3.  European Environment Agency, http://www.eea.europa.eu/soer/synthesis/synthesis/chapter5.xhtml!

4.  Price, Anne and Ariel Godwin, “Mapping Transportation and Health in the United States”. Planetizen, Jan. 16, 2012, http://www.planetizen.com/node/53728 !

5.  Voss, J.D. et al. “Association of elevation, urbanization and ambient temperature with obesity prevalence in the United States”, International Journal of Obesity (2013) 37, 1407-1412

6.  Lhamo Y. Sherpa et al., “Obesity in Tibetans Aged 30–70 Living at Different Altitudes under the North and South Faces of Mt. Everest “, Int J Environ Res Public Health. 2010 Apr; 7(4): 1670–1680.

7.  M. Ezzati et al., “Altitude, life expectancy and mortality from ischaemic heart disease, stroke, COPD and cancers: national population-based analysis of US counties. J. Epidemiology & Community Health, 2012


REFERENCES Hypoxia health effects and mechanisms 8.  Urdampilleta, Aritz et al., “Usefulness of intermittent hypoxia and exercise in obesity”, J Physiol

Biochem DOI 10.1007/s13105-011-0115-1

9.  Lippl, Florian J. et al. “Hypobaric Hypoxia Causes Body Weight Reduction in Obese Subjects”, Obesity (2010) 18, 675–681. doi:10.1038/oby.2009.509

10.  M. Ezzati et al., “Altitude, life expectancy and mortality from ischaemic heart disease, stroke, COPD and cancers: national population-based analysis of US counties. J. Epidemiology & Community Health, 2012

11.  Benjamin D. Levine, “Intermittent Hypoxic Training: Fact and Fancy”, High Altitude Medicine & Biology, 6 July 2004, 3 (2); 177-193.

12.  Messenger, S.A., and Cinello, j. “Effects of intermittent hypoxia on leptin signaling in the carotid body”, Neuroscience 232:216-225 (March 1, 2013)

13.  Zhu, Xin-Hong et al., “Intermittent Hypoxia Promotes Hippocampal Neurogenesis and Proucdes Antidepressant-Like Effects in Adult Rats”, J. Neuroscience, 22 September 2010, 30 (30: 12653-12663.

14.  Dourangsone D. Vadysinsak and Leif W. Ellisen, “mTOR under hypoxia”, Methods Mol. Biol.2012: 821: 45-58. doi: 10.1007/978-1-61779-430-8_4


REFERENCES Hormetic control of metabolism and health 15.  Cantó, Carles, and Johan Auwerx. “PGC-1alpha, SIRT1 and AMPK, an Energy Sensing Network That

Controls Energy Expenditure.” Current opinion in lipidology 20.2 (2009): 98–105. PMC. Web. 24 July 2016.

16.  Fernandez-Marcos, Pablo J, and Johan Auwerx. “Regulation of PGC-1α, a Nodal Regulator of Mitochondrial Biogenesis.” The American Journal of Clinical Nutrition 93.4 (2011): 884S–890S. PMC. Web. 24 July 2016.

17.  Blagosklonny, Mikhail . “Hormesis does not make sense except in the light of TOR-driven aging” Aging (Albany NY). 2011 November; 3(11): 1051–1062

18.  Emily E. Noble et al., “The lighter side of BDNF”, Am. J. Physiol Regul Integr Comp Physiol. 2011 May, 300 (5): R10530R0169, doi: 10.1152/ajpregu.00776.2010

19.  Madeo, Frank et al., “Can autophagy promote longevity?” Nature Cell Biology 12 (9) Sept. 2010: 842-846

20.  Gifford, Bill. “Spring Chicken”, 2015.

21.  Becker, Todd. “Live Longer!”, Getting Stronger blog, 31 March, 2015.

22.  Alistair V. Nunn et al., “Inflammatory modulation of exercise salience: using hormesis to return to a healthy lifestyle” Nutrition & Metabolism 2010, 7:87. http://www.nutritionandmetabolism.com/content/7/1/87



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