Amy Savagian MD
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My hope with these posts is to empower others.  I  want to share my interests: those things that enthrall me and I think will interest you.  The posts are not meant to give medical advice, but is meant simply to share the information related to health, wellness and longevity that I find fascinating right now. The first four posts starting October 2019 are the foundation for my lifestyle medicine practice.

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Lifestyle Medicine

2/24/2023

 
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The foundation of this practice is lifestyle medicine. Lifestyle medicine uses lifestyle factors to promote healthy aging.  The 4 drivers of healthspan and longevity are:


  • Activity
  • Sleep
  • Nutrition
  • & Mental Wellbeing


Below, I will discuss each of these fundamentals: 


Activity is the single most important factor of healthspan. We have seen that even 10 minutes a day of exercise could add years to a person's life (Church, 2007). And perhaps less newsworthy, but certainly interesting, was a study published in 2014 that showed runners were far less likely to die of heart disease regardless of BMI or smoking status (Artero, 2014). In an article published in the Journal of the American Medical Association, the Cleveland Clinic analyzed 23 years of patient data and 122,007 patients. They evaluated the association of all-cause mortality (death for any reason) and cardiorespiratory fitness. They also evaluated age, gender, race/ ethnicity, and co-morbidities such as diabetes, hypertension, smoking and coronary artery disease (CAD).

The findings were remarkable. Their findings on typical risk factors were consistent with what we often see. Having diabetes, CAD, smoking, or hypertension conferred approximately a 1.2-1.4X mortality risk or an approximately 20-40% increase risk of death from any cause, but here is the remarkable aspect, being out of shape or having low fitness conferred a 5.0X mortality risk that is a 400% increase risk of death from any cause over any time period. In other words being out of shape was 3 to 4 times worse than smoking, having diabetes or having CAD.  (Mandsager, 2018) (For more information see my post on VO2 max)

Sleep
Sleep has become the new currency. Studies have shown that adequate sleep lowers the risk of some cancers (Thompson, 2011; Irwin,1994; Hakim, 2014), the risk of diabetes (Knutson,2007; Sheen,1996)  and helps maintain heart health. One study showed that 6 or less hours of sleep led to a 200-300% increased risk of coronary artery calcification (King, 2008). Proceedings of the National Academy of Sciences (PNAS) published an article that found limiting sleep to less than 6 hours for 1 week changed the activity of 711 genes or about 3% of the total genome (Möller-Levet, 2019). It found that the sleep reduction down-regulated genes that were associated with healthy immune functioning and up-regulated genes associated with chronic inflammation and tumor production. (For more information see my post on sleep.)


Nutrition:
Nutrition is a loaded term. It has a different meaning to different groups of people. From a healthspan perspective, there are many ways to eat well. I believe the most important thing we can do is to keep sugars low. According to the 2010 Dietary Guidelines advisory committee our top sources of calories for North Amercians come from: 

  1. Grain-based desserts (cakes, cookies, donuts, pies, crisps, cobblers, and granola bars)
  2.  Yeast breads
  3.  Chicken and chicken-mixed dishes
  4.  Soda, energy drinks, and sports drinks
  5.  Pizza
  6.  Alcoholic beverages
  7.  Pasta and pasta dishes
  8.  Mexican mixed dishes
  9.  Beef and beef-mixed dishes
  10.  Dairy desserts
 

When our top sources of calories are grain based desserts, processed foods and sodas, we are setting ourselves up for long term health consequences. High sugar foods and processed foods containing sugars are known risk factors for diabetes, obesity, metabolic syndrome, cancers, autoimmune diseases and chronic inflammation (Ma, 2022). Once we have minimized sugars  we can begin to look at timing and quantity of food, fiber and protein intake based on genetics, labs, activity and goals. (For more information please see this post.)

Emotional health and mental wellbeing:
Maintaining emotional health takes many forms. There is no one size fits all. For some meditation may be an important factor for others, community gives them a sense of wellbeing.  

Meditation practices as short as 3-4 minutes have been shown to increase parasympathetic tone, decreasing our sympathetic tone with improvements seen in blood pressure, immune function and digestion (Creswell, 2017).  Many studies demonstrate that meditation can change the balance of our autonomic nervous system (the part of our nervous system we don’t control)  from that of fight or flight (sympathetic) to that of rest, healing and digestion (parasympathetic) (Koopman, 2011; Amihai, 2015).  When our sympathetic nervous system is over activated for days, weeks or months we experience more stress and our bodies experience more inflammation (Bellinger, 2018).

Community has also been implicated in longevity. Many years ago there was a town in Pennsylvania where people seemed to have unusual longevity. Harvard researchers looked for many years as to why these people had such unusual longevity.  They evaluated the foods, water, genetics among other things and could not find anything that differed significantly from neighboring towns, except, that this town had an unusually strong family and community relationships. Sadly, over the years, as the town modernized and the cohesiveness dissolved, the longevity seen in this town regressed to that of neighboring towns (Egolf,1992). (For more information on mental wellbeing please see this post.)

Lifestyle medicine is meant to be practiced as a form of preventative not reactive medicine. While it is helpful to start lifestyle measures at any point, it is optimal to start early with relative consistency, understanding perfection is not possible.

I hope you found this helpful.

Amy Savagian, MD


References:


Amihai, I., Kozhevnikov, M. (2015). The Influence of Buddhist Meditation Traditions on the Autonomic System and Attention. Biomed Res Int. 731579. Published online 2015 Jun 4. doi: 10.1155/2015/731579

Artero EG, Jackson AS, Sui X, Lee DC, O'Connor DP, Lavie CJ, Church TS, Blair SN.  (2014). Longitudinal Algorithms to Estimate Cardiorespiratory Fitness: Associations with Nonfatal Cardiovascular Disease and Disease-Specific Mortality.  Journal of the American College of Cardiology, Jun, 63 (21):2289-96. doi: 10.1016/j.jacc.2014.03.008. Epub 2014 Apr 2.  

Bellinger, D.L.1, Lorton, D. (2018). Sympathetic Nerve Hyperactivity in the Spleen: Causal for Nonpathogenic-Driven Chronic Immune-Mediated Inflammatory Diseases (IMIDs)? Int J Mol Sci. 2018 Apr; 19(4): 1188. Published online 2018 Apr 13. doi: 10.3390/ijms19041188

Church TS, Earnest CP, Skinner JS et al. (2007). Effects of Different Doses of Physical Activity on Cardiorespiratory Fitness Among Sedentary, Overweight or Obese Postmenopausal Women With Elevated Blood Pressure: A Randomized Controlled Trial. Journal of the American Medical Association JAMA, 297(19), 2081-2091. https://jamanetwork.com/journals/jama/fullarticle/1108370

Creswell, David J. (2017). Mindfulness Interventions. Annual Review of Psychology. Vol. 68:491-516 (Volume publication date January 2017). First published online as a Review in Advance on September 28, 2016. https://doi.org/10.1146/annurev-psych-042716-051139

Egolf B, Lasker J, Wolf S, Potvin L. The Roseto effect: a 50-year comparison of mortality rates. Am J Public Health. 1992 Aug;82(8):1089-92. doi: 10.2105/ajph.82.8.1089. PMID: 1636828; PMCID: PMC1695733.

Hakim et al., (2014). Tumors grow more in sleep deprived mice: Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling. Cancer Res. Mar 1;74(5):1329-37. doi: 10.1158/0008-5472.CAN-13-3014

Irwin et al., (1994). “Sleep deprivation reduces natural killer cells: Partial sleep deprivation reduces natural killer cell activity in humans. Psychosomatic Medicine. 56(6):493–498. 


King et al. (2008). Short sleep duration and incident coronary artery calcification. JAMA 300(24):2859-66. doi: 10.1001/jama.2008.867.

Knutson et al. (2007). The metabolic consequences of sleep deprivation. Sleep Medicine Reviews. Volume 11, Issue 3, Pages 163-178. https://doi.org/10.1016/j.smrv.2007.01.002 

Koopman, F.A., Stoof, S. P., Straub, R. H. , van Maanen, M. A. , Vervoordeldonk, M. J. , Tak,  P. P. (2011) Restoring the Balance of the Autonomic Nervous System as an Innovative Approach to the Treatment of Rheumatoid Arthritis. Mol Med; 17(9-10): 937–948. Published online 2011 May 20. doi: 10.2119/molmed.2011.00065


Ma X, Nan F, Liang H, Shu P, Fan X, Song X, Hou Y, Zhang D. Excessive intake of sugar: An accomplice of inflammation. Front Immunol. 2022 Aug 31;13:988481. doi: 10.3389/fimmu.2022.988481. PMID: 36119103; PMCID: PMC9471313.

Mandsager K, Harb S, Cremer P, Phelan D, Nissen SE, Jaber W. (2018) Association of Cardiorespiratory Fitness With Long-term Mortality Among Adults Undergoing Exercise Treadmill Testing. JAMA Network Open. 1(6):e183605. doi:10.1001/jamanetworkopen.2018.3605
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2707428

Möller-Levet CS et al. 2019 Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome. Proc Natl Acad Sci U S A. Mar 19;110(12):E1132-41. doi: 10.1073/pnas.1217154110.

Sheen et al. (1996). Relationships between sleep quality and glucose regulation in normal humans. American Journal of Physiology. Volume 271, No 2,  01 AUG 1996. https://doi.org/10.1152/ajpendo.1996.271.2.E261-E270.

Thompson et al., (2011). Colorectal cancer and sleep: Short duration of sleep increases risk of colorectal adenoma. Cancer. Feb 15;117(4):841-7. doi: 10.1002/cncr.25507.
https://pubmed.ncbi.nlm.nih.gov/20936662/

​

Cognitive Health & Prevention of Dementia

2/4/2023

 
Cognitive health is one of our most valuable assets, and a large part of improving healthspan is staving off cognitive decline. The majority of my patients have normal cognitive function and would like to prevent cognitive decline.

Why is cognitive health an important focus? Approximately one-third of individuals 65 years and older had dementia or mild cognitive impairment (MCI) [Jama]. According to Alzu.org, a website put together by doctors at Weill-Cornell, up to 40% of MCI and dementia cases are preventable. Interestingly even in those whose dementia may not be entirely preventable, it may be possible to delay the onset symptoms. 

The area of risk reduction or preventing cognitive decline is very new and it is changing quickly.  At our practice we start by taking a good clinical history and looking at the ABC’s (Anthropometrics, blood biomarkers and cognitive functioning. This allows us to do a risk assessment and early intervention.  

Examples of anthropometrics include BMI, muscle and body fat evaluations. Blood biomarkers include markers of metabolism such as hemoglobin A1c and cholesterol, markers of inflammation such as hs-crp and genetics such as APOe4. The cognitive testing that we perform is using a platform called CNS Vital Signs. This tests areas of cognition such as processing speed, motor speed, memory and executive function. Below is a sample report of this testing.

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What can we do to optimize cognitive health? We first need to generally understand the mechanisms that are believed to contribute to cognitive decline.  These include: abnormal glucose metabolism, inflammation, oxidative stress, poor trophic factor signaling, and dysfunctional calcium flux (Isaacson et al 2018). In the section below I will discuss each of these and then lifestyle factors that may modulate the mechanisms contributing to cognitive decline.

Abnormal glucose metabolism:
Poor glucose metabolism, as seen in diabetes and overfed states such as obesity are known to contribute to insulin resistance at the level of the neuron. Type 2 diabetes is generally a state of hyperinsulinemia (high insulin). This state promotes neuronal inflammation and amyloid deposition. Interestingly, a high-fat, low-carbohydrate ketogenic diet, which is known to limit insulin production, in mice that genetically over-express amyloid beta resulted in a 25% reduction of amyloid burden compared to mice on a standard diet (Van der Auwera et al., 2005).

Inflammation:
Inflammation is also thought to worsen cognitive function. Studies have shown elevated inflammatory markers in patients with Alzheimer's Disease (AD). To modulate this inflammation, we can consider decreasing dietary sugars, adding in medications or supplements to decrease inflammation and assuring adequate sleep (as sleep deprivation increases biomarkers of inflammation) (Irwin et al., 2006). Social engagement may also play a role in decreasing the risk of AD by improving immune function (Bower et al., 2003, Friedman et al., 2007).

Oxidative stress: 
Patients with AD show many signs of oxidative stress including protein and DNA oxidation as well as lipid peroxidation. The increased oxidation comes from reactive oxygen species (ROS). ROS is important for normal cellular activity, but when there is an imbalance between the production and clearance of ROS the cell undergoes oxidative stress. People with APOe4 have increased markers of oxidative stress (Jofre-Monseny et al., 2008). To decrease oxidative stress, we need to increase the clearance of ROS or decrease the production.  

Trophic Factors: 
Trophic factors are basically growth factors. They include molecules such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) that are responsible for brain plasticity and improving cellular survival by preventing activation of the caspase system. BDNF is particularly important in the hippocampus (where  memory consolidation occurs). In AD, people have less trophic factors, which in the presence of increased amyloid can lead to neuronal death. (Guo et al., 1997)

Amyloid burden:
In AD, patients are known to have increased extracellular amyloid.  The role of amyloid is not fully understood–some people liken it to scar tissue, but as it accumulates, it causes more inflammation and increases oxidative stress. Interestingly, the oxidative stress, impaired glucose metabolism and inflammation can also lead to more amyloid deposition.

Dysfunctional calcium signaling:
In AD we see increased intracellular and mitochondrial calcium. These elevated levels can increase ROS, leading to increased oxidative stress, inflammation and amyloid production. Together this leads to increased rates of cell (neuronal) death. 

Reducing risk should have a multi-factorial approach.  Each approach may reduce risk across several domains. For example treating insulin resistance may help with glucose metabolism and downstream effects of inflammation and oxidative stress. Watson and Craft (2003) demonstrated that treating insulin resistance may reduce the risk of AD.

Targeted nutrition can reduce the risk of AD through mechanisms of insulin resistance, inflammation and oxidative stress. We can improve insulin resistance by reducing processed sugars and the overfed state. Diets such as a mediterranean or low carb diet have been shown to be helpful.  (Scarmeas et al., 2009, Volek et al., 2004).

Sleep deprivation has been shown to increase inflammatory cytokines. Assuring adequate sleep will decrease inflammation, improve insulin resistance and help with calcium toxicity. 

Stress management can help reduce cortisol levels that impact insulin resistance, oxidative stress, trophic factors, calcium toxicity and amyloid burden.

Exercise both resistance and aerobic helps with glucose metabolism, insulin resistance, oxidative stress and trophic factors.

Hormone replacement may lower amyloid burden and improve trophic factors. 

Drugs can target inflammation, oxidative stress and amyloid.  

Supplements may also play a role as it relates to insulin resistance, inflammation, oxidative stress and calcium toxicity.

Based on cognitive testing results we may also consider specific interventions that engage executive planning, motor speed, processing speed and more.

Alzheimer’s and mild cognitive impairment has a long window of brain changes before any symptoms arise. With monitoring and a targeted lifestyle plan, we can significantly reduce the risk of dementia.

References:
Alzheimer's Universe. Weill Cornell Medicine. Retrieved November 30, 2022, from https://www.alzu.org/.
 
Bower, J. E., Kemeny, M. E., Taylor, S. E., and Fahey, J. L. (2003). Finding positive meaning and its association with natural killer cell cytotoxicity among participants in a bereavement-related disclosure intervention. Ann. Behav. Med. 25, 146–155. doi: 10.1207/S15324796ABM2502_11
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Friedman, E. M., Hayney, M., Love, G. D., Singer, B. H., and Ryff, C. D. (2007). Plasma interleukin-6 and soluble IL-6 receptors are associated with psychological well-being in aging women. Health Psychol. 26, 305–313. doi: 10.1037/0278-6133.26.3.305
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Guo, Q., Sopher, B. L., Furukawa, K., Pham, D. G., Robinson, N., Martin, G. M., et al. (1997). Alzheimer’s presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid β-peptide: involvement of calcium and oxyradicals. J. Neurosci. 17, 4212–4222.
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Isaacson et al. Mechanisms of Risk Reduction in the CLinical PRactice of Alzheimer’s Disease Prevention. Front. Aging Neurosci., 10 April 2018.doi: 10.3389/fnagi.2018.00096
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Irwin, M. R., Wang, M., Campomayor, C. O., Collado-Hidalgo, A., and Cole, S. (2006). Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch. Intern. Med. 166, 1756–1762. doi: 10.1001/archinte.166.16.1756
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Jofre-Monseny, L., Minihane, A. M., and Rimbach, G. (2008). Impact of apoE genotype on oxidative stress, inflammation and disease risk. Mol. Nutr. Food Res. 52, 131–145. doi: 10.1002/mnfr.200700322
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Manly JJ, Jones RN, Langa KM, et al. Estimating the Prevalence of Dementia and Mild Cognitive Impairment in the US: The 2016 Health and Retirement Study Harmonized Cognitive Assessment Protocol Project. JAMA Neurol. 2022;79(12):1242–1249. doi:10.1001/jamaneurol.2022.3543
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Van der Auwera, I., Wera, S., Van Leuven, F., and Henderson, S. T. (2005). A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer’s disease. Nutr. Metab. 2:28.
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Volek, J. S., Sharman, M. J., Gómez, A. L., DiPasquale, C., Roti, M., Pumerantz, A., et al. (2004). Comparison of a very low-carbohydrate and low-fat diet on fasting lipids, LDL subclasses, insulin resistance, and postprandial lipemic responses in overweight women. J. Am. Coll. Nutr. 23, 177–184. doi: 10.1080/07315724.2004.10719359
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Watson, G. S., and Craft, S. (2003). The role of insulin resistance in the pathogenesis of Alzheimer’s disease. CNS Drugs 17, 27–45. doi: 10.2165/00023210-200317010-00003
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