living high and healthy - getting stronger · 2016. 8. 21. · • weight (bmi) and blood pressure...
TRANSCRIPT
Todd Becker
Ancestral Health Symposium
Boulder, Colorado
August 12, 2016
LIVINGHIGHANDHEALTHY
WhyColoradansandotherswholiveathighal>tudelivelonger,
andwhatflatlanderscanlearnfromthem
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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?
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WHY IS OBESITY SO LOW IN BOULDER?
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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
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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?
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• 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
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“Maps of Trends in Diagnosed Diabetes and Obesity”, Centers for Disease Control https://www.cdc.gov/diabetes/statistics/slides/maps_diabetesobesity_trends.pdf!
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THE DECADAL INCREASES ARE STRIKING BUT UNEVEN ACROSS THE STATES
“Maps of Trends in Diagnosed Diabetes and Obesity”, Centers for Disease Control https://www.cdc.gov/diabetes/statistics/slides/maps_diabetesobesity_trends.pdf!
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COLORADO AND A FEW OTHER STATES ARE BUCKING THE TREND…BUT WHY?
“Maps of Trends in Diagnosed Diabetes and Obesity”, Centers for Disease Control https://www.cdc.gov/diabetes/statistics/slides/maps_diabetesobesity_trends.pdf!
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/ !
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…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
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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
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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
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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.
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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
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• 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 (+)
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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
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• 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
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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
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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?
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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
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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
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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
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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
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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)
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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
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• 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
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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?
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THREE THEORIES OF AGING
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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
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• 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!
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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
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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
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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
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• 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
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Hormesis
Mitochondria
Energy
Inflammation
Exercise Eating
Exercise Cold/hot Calorie restriction Polyphenols
Sedentary life Comfort Caloric excess Inflammatory foods
VICIOUS CYCLE OF INFLAMMATION
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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?
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“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
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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
COPYRIGHT TODD BECKER 2016
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
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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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QUESTIONS?