Amy Savagian MD
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Research & Posts

This page is about my current interests and research.  My hope with these posts is to empower others.  I  want to share the research I am engaging with now and 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 are the foundation for my lifestyle medicine practice.

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COVID Vaccine

1/6/2021

 
Happy New Year!

I have had many patients emailing and calling to inquire about the COVID vaccine. As of now vaccines are only being administered through long term care facilities, hospitals and hospital clinics.  Walgreens and CVS are providing the first phase of vaccines at long term care facilities.  

Initial distribution outside of long term care facilities and hospitals is currently planned to be through pharmacies based on age, risk and job. Below are the planned phases of distribution. 
Phase 1A
  • Healthcare workers
  • Long-term care residents
1B Tier One:
  • Individuals 75 and older
  • Those at risk of exposure at work in the following sectors: education, childcare, emergency services, and food and agriculture
1B Tier Two:
  • Individuals 65 -74 years of age
  • Those at risk of exposure at work in the following sectors: transportation and logistics; industrial, commercial, residential, and sheltering facilities and services; critical manufacturing
  • Congregate settings with outbreak risk: incarcerated and homeless
Phase 1C
  • Individuals 50 -64 years of age
  • People 16-64 years of age and have an underlying health condition or disability which increases their risk of severe COVID-19
  • Those at risk of exposure at work in the following sectors: water and wastewater; defense; energy; chemical and hazardous materials; communications and IT; financial services; government operations / community-based essential functions


Currently approved we have the Pfizer-BioN Tech and Moderna vaccines that must be given 3-4 weeks apart. It is currently unknown when phase 1b will begin.  It will likely not start until March.

Community distribution of the vaccine will be available locally through Albertsons, CVS, Rite-Aid, Target, Walgreens, Costco and Walmart.

While all of the above will be offering the vaccines, Albertsons has a sign up link for current updates: https://www.albertsons.com/pharmacy/covid-19.html  and 
CVS has a scheduling tool that will be used once the vaccine is available outside of phase 1a: https://www.cvs.com/immunizations/get-vaccinated

Lastly, once the vaccine is available outside of phase 1a, Vaccinefinder.org is also a helpful link to locate the vaccine in any community.

For more information please look to official sources such as California for all or the CDC COVID pages for more detailed information.  Details are changing rapidly so please check back with the CDC or ca.gov sites above.  Lastly for anyone that falls into phase 1B or 1C you will be able to schedule your appointment through LA County Public Health at the appropriate time.  Currently, this site only applies to healthcare workers. I have applied to have vaccines for my patients, though this would not likely happen until this summer and higher priority patients will likely be provided the vaccines ahead of that by LA County.

.
Best,

Amy 
Amy Savagian, MD

SARS-CoV-2 CDC Fatality Rate Update

5/25/2020

 
The CDC has newly released estimates on fatality, hospitalization, and other biologic characteristics of SARS-CoV2.  [https://www.cdc.gov/coronavirus/2019-ncov/hcp/planning-scenarios.html] The most interesting and potentially reassuring take away is that the CDC’s best estimate now lowers the fatality rate significantly. Below is a table from the CDC listing five scenarios of best, worst and current estimates.

The CDC is estimating an overall fatality rate around 0.4%. This is much lower than the up to 13% death rate coming out of Italy.  Before going deeper in the numbers, I want to take take a moment to say that while we speak of death rates, and reassurance, each of these statistics is based on people who died, people who had friends and family that love them.  My heart goes out to the victims, their friends and family.


While the overall death rate is being projected at 0.4%, it is important to note that this is composed of very different rates across age. For those under 50 years of age the average death rate is extremely low, estimated to be 0.05%. For those 50-64 years of age the fatality rate is now thought to be 0.2%, and for those over 65 years the case fatality rate is estimated to be 1.3%. For reference, 0.2% is the fatality rate of measles in the US, one of the vaccines many Americans refuse.
​[
https://www.cdc.gov/vaccines/pubs/pinkbook/meas.html]

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To put this further  into perspective, I thought it may be useful to look at a person's chance of death of any cause in a given year.  This data comes from our government and is called a life table.  [https://www.ssa.gov/oact/STATS/table4c6.html]. 

After the age of 22, the chance of death from any cause in these age groups appears to remain higher than the SARS-CoV-2 estimated fatality rate. For example a 50 year old has a 0.4% chance of dying of any cause and a 0.2% chance of dying of COVID-19. A 70 year old has a 1.88% chance of dying of any cause and a 1.3% chance of dying of COVID-19.
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Does this mean we can be completely free of masks and begin holding large events? Sadly, though the fatality rate is low, I don’t think the data otherwise supports that.  The hospitalization/ICU rate is what I think should drive many decisions.

The CDC estimates hospitalization rate by age from 1.7% to 7.4% with an overall hospitalization rate of 3.4% and of those between 21%- 29% will need to go to the ICU. To illustrate why this is problematic, first consider the US population of 330M, if hospitalization occurs regularly until herd immunity at an estimate of 66%, it means over 5M Americans would need to be hospitalized and over 2M would need ICU care.

With only about 63,000 ICU beds [Total less neonatal, pediatric and cardiac ICUs] https://www.aha.org/statistics/fast-facts-us-hospitals in the US and potentially over 15M ICU days needed if the disease ran its course unchecked until we reached herd immunity, excess deaths from SARS-CoV2, stroke, heart attack and other causes would likely occur as care could be unavailable. ICU availability is still our biggest weakness as our ICU’s could be over-run as we saw in Italy.


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​While I do not think we should be hosting large events, I do not think we should necessarily live in a bubble.  I like the Michael Olsterholm approach of attempting to thread the rope through the needle. Slow openings to allow a slower course hopefully preventing excess deaths.


I have spent a great deal of time suggesting that we need to be aware of misinformation.  Please check references.  Social media is not a great platform for an accurate information.  Some news outlets may also not be portraying accurate information in order to grab viewers.  I find often that news outlets either don't have enough science writers or they attempt to get better viewership by sensationalizing the headline. For great information on SARS-CoV-2. Please consider looking to:


CDC: https://www.cdc.gov/coronavirus/2019-ncov/index.html
CIDRAP/ Olsterholm Report: https://www.cidrap.umn.edu/covid-19
Hospital and university news updates such as:  
​
https://www.hsph.harvard.edu/coronavirus/covid-19-news-and-resources/

I hope this is helpful to you!!

~Amy 

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SARS-CoV-2 Update on Antibody Testing

4/28/2020

 
This Covid update is more  optimistic than past updates.  The data is changing rapidly and this will change the outlook and recommendations as they become outdated.  Today, I am going to discuss how some studies are suggesting that SARS CoV 2 is much more wide spread than we realized which implies a much lower fatality rate. I also want to share information on antibody testing including, which tests are good and the importance of choosing an accurate test.  

The below graphic is a slide I prepared for a few decision makers on 4/26/20. It evaluates case hospitalization and case fatality rates in LA County vs potential infection hospitalization and fatality rates in LA County.  The difference between case and infection rates are based on studies using antibody testing. The chart and graph evaluate the number of hospitalizations and deaths as of 4/26 relative to the  potential infections based on the multiples from the NY data and the USC study.​
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​In New York City, the rate of cases vs infections presented by Gov. Cuomo was approximately a multiple of 12, suggesting a much lower infection fatality rate. In Los Angeles, USC completed a study using antibody testing suggesting the we had 28-55 times more infections that cases reported. These are in-line with the Stanford/ Santa Clara study suggesting they had 50X more infections that cases reported. All of these studies optimistically show a much lower hospitalization and fatality rate.  Having said that, there are problems with the antibody tests, so we need to evaluate these tests and studies with some healthy skepticism. 

For my patients, I am offering the Quest RT-PCR for active symptoms and the Abbott serology test to evaluate prior exposure.  The Abbott serology test has been tested internally at Abbott and through a separate commercial lab. From internal testing Abbott reports a sensitivity of 100% and a specificity of 99.5%.  The outside lab validated the prior testing suggesting a sensitivity of 100% and a specificity of 99.4%. When evaluating antibody tests, the accuracy is very important as many of these tests are not very accurate.  The specificity of these tests is the more important parameter, as you want as few false positives as possible.

If you are not a patient of mine, but are interested in antibody testing, the FDA has given letters of authorization to some companies.  Click here for a complete list.  [https://www.fda.gov/medical-devices/emergency-situations-medical-devices/emergency-use-authorizations#covid19ivd]

With any of the tests, they should be done in conjunction with a conversation with your doctor.  The antibodies show past exposure.  The antibody seems to offer a window of protection, though there are questions related to seroconversion and the permanence of immunity after developing antibodies.

On a separate note, I wanted to include some educational links to excellent talks on SARS-CoV-2.

The first is by Dr. Olsterholm from the MN Center of Infectious Disease Research and Policy (CIDRAP)  He has 5 excellent podcasts thus far and many webinars available at this site. https://www.cidrap.umn.edu/covid-19/podcasts-webinars

The second excellent educational talk on SARS-CoV-2 is by Dr. Pamela Bjorkman a Cal-tech professor whose lab is currently evaluating the virus.  https://www.youtube.com/watch?v=OBcc_dk9Q9U

Be well,


Amy

Covid-19: How Does It End?

4/15/2020

 
Let’s start with good news. In California, we have definitely “flattened the curve.” We are approximately 90% below my projections from the LAC data from 3/22 and 3/28. Our doubling time has significantly increased, and we are off our exponential curve.
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I have been postponing putting out this aspect of my analysis for a week now. Everyday things seem to change, and I hoped my analysis would lead me elsewhere.  I want to spend a minute discussing what flattening the curve means,  what different aspects of the curve means and why I think we will have periods of self isolation/ social distancing and re-socialization over at least the next year.

The curve represents cases over time. The area under the curve represents the total number of cases.  By flattening the curve, we prevent hospitals from being overwhelmed. But it doesn’t mean we ”eradicate” the disease. We live in a globalized society where international travel still occurs and people can travel state to state.  If we don’t want to overwhelm the medical system and the number are correct, flattening the curve means we push out our time-line. It means this ends by one of three ways, we have a vaccine, we have an effective treatment or we reach herd immunity (which is thought to occur when about 2/3’s of the population has had the disease). 

Herd immunity, assuming the numbers are correct is several years away.  I think we will have a vaccine or treatment first.  So what does this mean?  I think it means we will go through multiple periods of social-distancing/ self isolation and re-socialization.  I’m hoping our numbers are wrong and that we are significantly underestimating the number of cases we have had. There are two main factors that give me hope.   In Iceland, half the people that have tested positive were asymptomatic and if Covid began in China in November and it has the transmissibility that it seems to have, hopefully many more people have had it than have realized it.
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Let's walk through a scenario below of how LA County could reach herd immunity without overwhelming the system, and you will see why I think we will have a vaccine or treatment before herd immunity and why this won't be over in a few months, but we will likely see multiple cycles of social distancing and re-socialization.  
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We know that LA County has 10.1M people this means we need about 6.7M cases of covid to reach herd immunity. If we assume 5% of cases need a ventilator that means we will have 336,602. people needing a vent.  Average duration on vent has been variable depending on data-sets, but let's assume the average person who needs a vent requires it for 12 days. 336,602 x 12 is about 4M vent days required.  Gov. Newsom has called for 10,000 vents in CA, that means we should have about 2500 in the LA area.  If we divide 4M vent days by 2500 vents we will get the number of days required to reach herd immunity without overwhelming the system.  The answer is about 4 years.  That assumes we have our numbers of cases correct, which is a big if.  Harvard public health came out yesterday suggesting a similar scenario, though I am sure they had a much more eloquent model.  What this means if these numbers hold is that we have a long winter ahead, but with social distancing, we can prevent the system from being overwhelmed.

​
Be well,

Amy

COVID-19 Mortality, Risk Factors and Prevention

3/11/2020

 
Like most American's COVID-19 has my attention.  I am mainly looking to the WHO and CDC for my information.  Sadly, I feel like many of our news outlets are more interested in grabbing views than presenting balanced information.

What we know for sure, based on the Chinese data posted on the CDC website as of 3/11/20.
1. For those under 50, the mortality rate is very low 0.2-0.4% .
2. Across all ages (including 80 year olds) those people with no chronic illnesses also had a low mortality rate of 0.9%.
3. People over 80 years old had the highest death rate at 14.8%
4. Of confirmed COVID-19 patients in China as of Feb 11, 2020, only 2.1% were aged <20 years, and no deaths were reported among those <10 years of age .
5. An overall mortality rate of 2.3% has been reported among confirmed cases of COVID-19 in China. However, this is likely over-estimated as the majority of these cases were among hospitalized patients. (That means the denominator - the total number of case- likely did not include people that had mild symptoms and did not get tested)

Taken together, this means we need to be extremely protective of our elders and those with chronic conditions, but the average American does not need to panic.


Signs & Symptoms:
According to the CDC, frequent signs and symptoms of patients admitted to the hospital include fever (77–98%), cough (46%–82%), myalgia or fatigue (11–52%), and shortness of breath (3-31%) at illness onset. The incubation period may range from 2-14 days.

Transmission:
Thought to be droplet.  This means that the virus sits on tiny water drops that are expelled with a cough or sneeze.  It is not thought to be airborne or aerosolized at this time. People that most need masks are those who are sick and health care workers.  Those who are healthy do not need to wear masks unless they are caring for someone who is sick.


Virus Spread/Transmission:
The virus is spread mainly from person-to-person, between people who are in close contact with one another (within about 6 feet). It is spread through respiratory droplets produced when an infected person coughs or sneezes. These droplets can land in the mouths or noses of people who are nearby or possibly be inhaled into the lungs.

What we can all do.
1. Wash hands often and with soap (for 20 seconds- you can sing twinkle twinkle little star and this is about 20 seconds) or use hand-santizer with 60% alcohol.
2. Avoid touching eyes, nose and mouth with unwashed hands.
3. If COVID-19 is spreading in your community keep at least 6 feet between you and others.
4. Clean and disinfect commonly touched surfaces daily. This includes tables, doorknobs, light switches, countertops, handles, desks, phones, keyboards, toilets, faucets, and sinks.
5. For those that want to boost immune response to RNA viruses like influenza and corona viruses, there is a paper by Mark McCarty and James DiNicolantanio that outlines mechanistically how the following nutraceuticals taken daily as prevention may be beneficial.
Selenium 50-100mg
Zinc 30-50mg
Elderberry 600-1500mg
Lipoic Acid 1200-1800mg
Glucosamine 3000mg
Spirulina 15g
Yeast beta glutamates 250-500mg

Though, as always speak to your doctor before starting any supplement regimen.
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Going to the doctor's office office. 
If you have a mild upper respiratory infection you should stay at home.  If you need to be seen with an upper respiratory infection, please call ahead and let us know so that we can quickly get you into a room and take appropriate preventative actions without exposing other patients.


Should You Supplement NAD+?

1/23/2020

 
Some people have called NAD+ an  anti-aging miracle drug. In the last post I briefly mentioned that NAD+ is considered a longevity compound. NAD+ and its precursors are key compounds that Dr. David Sinclair focuses on in his lab at Harvard and that he personally takes daily.[1] In this post, I hope to share what NAD+ is, and why you may want to consider boosting your levels.

NAD+ is a vitamin B3 derivative. It is critical to every cell and is required for energy production and cellular repair. Think high-school biology, Krebs cycle and the Electron Transport Chain. NAD+ is necessary for moving electrons around, which allows us to generate the cellular energy of ATP. It allows us to extract cellular energy from carbohydrates, proteins, and fats.

In addition to energy production, NAD+ also turns on multiple longevity genes, especially the sirtuins.  The sirtuin family of genes are regulators of epigenetics. The sirtuins create enzymes that help keep DNA organized so the DNA can function properly. Sirtuins also help in the repair of damaged DNA, reduce inflammation, and help with stress resistance. As we age, our levels of NAD+ decline, and we have a corresponding decrease in sirtuin activity.  Some researchers suspect that replacing and replenishing NAD+ levels may help stem the aging process.

Some of the studied benefits of increasing NAD+ include:

1.  Improved heart health by decreased arterial stiffness and lower blood pressure. [3,4]
2. Improvement of mitochondrial and neuronal health. In an Alzheimers mouse model, NAD supplementation through precursors slowed cognitive decline. [5,6,7]
3. Life span extension in yeast, worms and rodents. [8,9]

You may wonder why many of the longevity studies on NAD+ are in animal models.  Animals have similar genetic and molecular pathways as humans and unlike humans they do not live as long.  A study in humans on longevity could take a century, whereas in animals the study could be done in 3-5 years. 

Most of the studied benefits with NAD+ have been demonstrated using oral precursors since oral NAD+ is not easily absorbed. An alternative delivery system, IV NAD+, has not been studied as thoroughly, though there are many reported benefits, which include improvements in: 

ADHD, 
executive function, 
addiction,
anxiety, 
depression, 
chronic fatigue and 
cognitive decline.

Given the studied and reported benefits, you may wonder how to increase your NAD+.
​We can maintain youthful levels of NAD+ by either:
1. Decreasing use/destruction of NAD+
2. Increasing production or levels of NAD+


NAD+ is consumed primarily by 1. PARPs (in DNA repair) 2. Sirtuins (as discussed above) and 3. CD-38 (to be discussed below). The largest consumer of NAD as we age appears to be CD-38.  CD-38 is a signaling molecule induced by zombie cells or senescent cells from molecules they secrete. If we want to increase our pool of NAD+ by decreasing usage, the primary target should be cd-38 and zombie cells. [10]

To decrease use of NAD+:
1. Minimize cellular stressors. This includes the boring truisms of reducing or eliminating smoking, eating real foods rather than processed, lowering your intake of sugar, getting enough sleep, and stress management.
2. Lower cd-38 levels. This can be accomplished by lowering the number of zombie cells.  The best way to lower the load is through the use of senolytics. Examples of senolytics include supplements like quercetin, fiscetin and curcumin. A promising animal trial at Mayo Clinic showed a significant reduction in zombie cells using a medication called Desatinib  and quercetin. [11]

NAD+ levels can be increased by: 
1. Fasting
2. Exercise
3. IV NAD+ and oral NAD+ precursors:
 Animal studies have shown that taking precursors can raise blood levels of NAD by 2.7X, [12] and human studies of IV NAD+ show that NAD+ is both safe and readily taken up by tissues. [13]

To bring it all together, NAD+ is important in energy metabolism and DNA repair. With age, our NAD+ levels fall, and we are more prone to age-related diseases.  NAD+ has been shown in humans to reduce the risk of some age-related diseases and in animals to extend their lifespan.  Though I am hoping to see more research in this area, given the low risk, good safety profile, and potential upside, I personally take oral NAD+ precursors and IV NAD.  As always, talk to your doctor before starting any supplements.

Hope you have enjoyed this,

Amy
References:
1.  Sinclair, David A and LaPlante, Matthew D.  2019 Lifespan: Why We Age and Why We Don’t Have To. NY, NY. Simon and Schuster.

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2. It takes two to tango: NAD+ and sirtuins in aging/longevity control, Shin-ichiro Imai,* and Leonard Guarente. NPJ Aging Mech Dis. 2016; 2: 16017). 

3. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. de Picciotto NE et al. Aging Cell. 2016 Jun;15(3):522-30. doi: 10.1111/acel.12461. Epub 2016 Mar 11 +

4. Nicotinamide riboside supplementation reduces aortic stiffness and blood pressure in middle-aged and older adults. MArtens, C et al. Artery Research Dec 2017 Vol 20:49.)  

5  Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model Long, A et al. BMC Neurology 15, no. 1 (March 2015).

6  The association between PGC-1α and Alzheimer's disease. Sweeney, G et al. Anat Cell Biol. 2016 Mar;49(1):1-6.

7. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Gong B et al. Neurobiol Aging. 2013 Jun;34(6):1581-8.)

8. The NADthplus/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling Mouchiroud, L. et al. Cell 154, no. 2 (July 2013): 430–41.

9. NAD+  repletion improves mitochondrial and stem cell function and enhances life span in mice Zhang, H. et al. Science 352, no. 6292 (April 2016): 1436–43. 

10. [CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism.  Camacho-Pereira, M.G. Tarragó, C.C.S. Chini, V. Nin, C. Escande, G.M. Warner, A.S. Puranik, R.A. Schoon, J.M. Reid, A. Galina, E.N. Chini, Cell Metabolism 23 (2016) 1127–1139]

11. The Multi-faceted Ecto-enzyme CD38: Roles in Immunomodulation, Cancer, Aging, and Metabolic Diseases. Hogan, K et al. Front Immunol. 2019; 10: 1187.

12. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.Trammell et al.  Nat Commun. 2016 Oct 10;7:12948.

13.(A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD+. Grant, R et al. Front Aging Neurosci. 2019; 11: 257.

Is Aging a Treatable Disease?

12/15/2019

 
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What has my attention right now?  Dr. David Sinclair of Harvard University has written a book called, “Lifespan: Why We Age and Why We Don’t Have To.” In the book, Dr. Sinclair states that aging is a disease, and that disease can be treated. 

This revolutionary idea turns conventional wisdom upside down.  What about aging gracefully?  After reading this, I wonder, as I see older friends pull out readers to decipher menus, might I avoid needing “readers” one day? And, Is Sinclair proposing a fountain of youth? Well, in a way, yes! 

Historically geneticists have thought that mutations in DNA and the subsequent loss of correct genetic code led to a disruption of cellular functioning producing aging as we know it.  Sinclair proposes that aging is not due a loss of genetic code, but rather a loss of how the genetic code is expressed (a change in the epigenetics).

This epigenetic information determines how one’s genetic code is expressed. To further explain epigenetics, he gives the example of a caterpillar turning into a butterfly, the genetic code of the insect doesn't change, only the expression of its genes change. 

He goes on to suggest that if our genetic code is like digital code, which is durable and easy to replicate, our epigenetic information can be likened to analog information, which is easily changeable and can act like scratches on a DVD (our digital code). He calls his theory, the information theory of aging. 

Here is the promising part: science is actually showing that our epigenetic changes resulting in aging are reversible. Back to our analogy, if our aged DNA is a scratched DVD, then they are finding a way to polish out the scratches.

The book is divided into three sections: the past, present, and future of aging research.  In other words, what we know, what we are learning, and where we are going. In the last section, Dr. Sinclair outlines his current daily routine which incorporates the lifestyle changes discussed in the last 4 posts and involves NAD boosters that activate our longevity genes and maintain our epigenetics.

NAD is a derivative of vitamin B3 that is required by every cell to turn on our longevity genes and to create energy in our mitochondria (the cell’s powerhouse). He discusses this molecule in great detail which we will explore further in the next post.​

Overall, “Lifespan” is a fascinating look into the frontiers of research showing that we can slow down, or even reverse, aging by activating our longevity genes. For anyone over 30, this is a must read.

Can Fasting Help You Play, Love & Live Longer?

11/19/2019

 
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This is the last week of our four part series on how to play hard, work hard, and be fully engaged with family, friends and community for as long as possible. 

As nutrition is one of the key components of longevity, I hoped this post/email would give you compelling data on the best way to eat, but what I have found, is that the most advanced research on nutrition and longevity is not about what types of foods you should or shouldn’t eat. Instead the best research seems to be on  fasting and caloric restriction, neither of which I realize, are very sexy. But the molecular mechanisms that they turn on are pretty amazing. Both signal our cells to clean house (autophagy), stimulate stem cells, change our epigenetics (the expression of our genetic code), change metabolic pathways, turn on longevity genes like the sirtuins, and improve our stress resistance.  [1,2,3,4] Each of these  improvements should help you to play, work and engage longer.

In my practice, I focus mainly on fasting as, honestly, long term caloric restriction (CR) is not sustainable or very fun. Studies like the one conducted in Biosphere 2, which relegated human volunteers for 24 months to severe CR, resulted in cold, irritable people with no sex drive. [5] However, fasting and intermittent fasting seems to hold a lot of promise, and while not appropriate for everyone, the studies are encouraging.

Fasting has specifically been shown to lower the risk of developing cancer, cardiovascular disease, and neurodegenerative disease. [6] Fasting cycles have been shown to work as effectively as chemotherapy in some tumors, and when combined with chemotherapy it appears to enhance the benefits and lower the chemo side-effects. [7] Fasting can also be a very effective way to lower high blood pressure. [8] Fasting has even been shown to improve verbal recall. [9]

A study by de Cabo suggested that eating patterns may play a larger role than diet composition. [10] This finding is particularly interesting given all of the debate around dietary restriction.  There are so many conflicting trials and so much conflicting information in the area of dietary restriction.  Mediterranean, low carb, low fat, paleo, keto, vegan and vegetarian all seem to have studies saying they are the best.  

What is right answer? Evidence suggests that when people stop eating the processed Standard American Diet (SAD) and move to a real foods plan (eating foods devoid of processed and sugary foods), any of these diet styles are an improvement. If we look at the top ten sources of American calories, grain-based desserts like cakes and cookies top the list followed closely by sugary drinks, alcoholic beverages and dairy desserts. [Source: Report of the 2010 Dietary Guidelines Advisory Committee]

Many patients have asked me about the Netflix show, “The Game Changers.” I propose that when we eliminate the processed and sugary foods and move to a real foods plan whether it’s keto, vegetarian, paleo, low fat or otherwise, we will begin to feel and perform better. If you want a balanced, well-considered perspective on “Game Changers” please see the Peter Attia article.

Getting back to longevity, we know there is a link between sugar and inflammation. You already know the painful consequences of inflammation when you overdo it at the gym, but what you may not be aware of is how inflammation impacts your system when you indulge in too much sugar. I generally suggest avoiding sugary foods such as sodas as well as most processed foods, which can be loaded with hidden sugars. Reducing your sugar intake reduces inflammation, which in turn may slow the aging process.

So how can you eat to live your best life? 

1. Eat “real” foods instead of processed. If you are buying things in box or a can, read labels for grams of sugar and check ingredients.  If you want to get deep in the weeds, I have found Rhonda Patrick's SNP analysis helpful in beginning to understand how different dietary and supplement approaches may affect you based on your genetic profile.

2. Intermittent fasting or time restricted eating may be part of a healthy longevity plan. A Stanford oncology trained friend of mine suggests everyone allow at least 12 hours every night between their last food of the night and breakfast. This allows for autophagy or cell cleaning to occur.

3. A good resource for learning more about how to fast is: “The Complete Guide to Fasting.” I also like the documentary “Eat, Fast, Live Longer.”

4. There are also fasting mimicking diets (FMD's). These are often 3-5 day plans that allow you to consume some food but make your body think it is fasting. Valter Longo a prominent researcher in this field has a commercially available plan called Prolon.  In humans, this FMD lowers inflammation markers, improves blood pressure, enhances cognitive performance, increases circulating stem cells by 800% and lowers biomarkers/risk factors for aging, diabetes, cardiovascular disease, and cancer. [11] Each of these improvements should lead to a longer, healthier life.

I personally like the 5 day FMD, Prolon as it has solid research supporting it. I think a five day plan is easy to finish and the perfect amount of time for a re-set.

-Amy





1.Fontana L, Partridge L, Longo V.D. Extending healthy life span—from yeast to humans. Science. 2010; 328: 321-326 
 2 Mattson, W, et al. Flipping the Metabolic Switch: Understanding and Applying Health Benefits of Fasting. Obesity (Silver Spring). 2018 Feb; 26(2): 254–268. doi: 10.1002/oby.22065
3.
 Haigis MC, Guarente LP. Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006 Nov 1;20(21):2913-21.
 
4. Madeo F, De Cabo R. Et al. The search for antiaging interventions: from elixirs to fasting regimens. Cell. 2014; 157: 1515-1526.
 5. Walford R.L. Mock D. Verdery R. MacCallum T. Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. J. Gerontol. A Biol. Sci. Med. Sci. 2002; 57: B211-B224.
 6. Longo V.D. Mattson M.P. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014; 19: 181-192. 
 7. Raffaghello L. Lee C. Safdie F.M. Wei M. Madia F. Bianchi G. Longo V.D. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc. Natl. Acad. Sci. USA. 2008; 105: 8215-8220.
 8. Goldhamer A.C. Lisle D.J. Sultana P. Anderson S.V. Parpia B. Hughes B. Campbell T.C.Medically supervised water-only fasting in the treatment of borderline hypertension. J. Altern. Complement. Med. 2002; 8: 643-650.

9. Madeo F. Et al. Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans. Cell Metabolism. 2019; 30: 3: 462-476.E5.
 10. de Cabo et al. Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories. Cell Metabolism, 2018; DOI: 10.1016/j.cmet.2018.08.011

11. Wei M, Brandhorst S, Shelehchi M, Mirzaei H, Cheng CW, Budniak J, Groshen S, Mack WJ, Guen E, Di Biase S, Cohen P, Morgan TE, Dorff T, Hong K, Michalsen A, Laviano A, Longo VD. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017 Feb 15;9(377). doi: 10.1126/scitranslmed.aai8700.

Other related studies:

Mattson M.P. et al. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc. Natl. Acad. Sci. USA. 2003; 100: 6216-6220

Panda S. et al. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 2014; 20: 991-1005

Longo, V.D., Panda S. Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell Metab. 2016; 23: 1048-1059

Minor R.K. Allard J.S. Younts C.M. Ward T.M., de Cabo R. Dietary interventions to extend life span and health span based on calorie restriction. J. Gerontol. A. Biol. Sci. Med. Sci. 2010; 65: 695-703

Longo et al.  A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan.
Cell Metab. 2015 Jul 7;22(1):86-99. doi: 10.1016/j.cmet.2015.05.012. Epub 2015 Jun 

Does Sleep Improve Longevity?

11/12/2019

 
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This week, we are exploring the research on sleep and longevity. This is the third in a four-part series on how to play hard, work hard, and be fully engaged with family, friends and community for as long as possible. [Click here to see the first two weeks posts]

For most of us, being fully engaged and productive often comes at the cost of a loss of sleep. In our productivity-driven culture people say they will “sleep when they are dead”, and from what I have read, those people will get their wish more quickly than they may like. Today, I hope to illustrate why getting at least 7 hours of sleep may be the magic pill to improving health, longevity, intelligence, sexuality, productivity, and likeability. 

Last week we talked about how meditation could change the balance of our autonomic nervous system, which is the part of our nervous system we don’t control from that of sympathetic (a.k.a fight or flight) to parasympathetic (a.k.a. rest, healing and digestion) [1,2]. When our sympathetic nervous system is overactivated for days, weeks or months, we experience more stress and our bodies experience more inflammation. [3] Sleep also helps lower sympathetic tone, which may have health benefits.
To help me understand the benefits of sleep better, I looked first to one of the most prolific researchers on sleep, Matt Walker of UC Berkeley. On a recent podcast Dr. Walker said, “If there is one central, common pathway through which we can understand almost all aspects of the deleterious impact of insufficient sleep, it is through the autonomic nervous system, and specifically an excessive leaning on the fight or flight branch of the nervous system.” To put it more simply, if the lack of sleep leads to more fight or flight, then this high sympathetic tone may be part of the reason we see poor sleep associated with poor immune function, heart disease and diabetes to name a few possible side effects. 

So what have the studies shown? From a health perspective, we have seen that adequate sleep lowers the risk of some cancers. [4,5,6]  Sleep also seems important for lowering risk of diabetes [7,8] and maintaining heart health. One study showed that 6 or less hours of sleep led to a 200-300% increased risk of coronary artery calcification. [9]

When considering longevity, PNAS (Proceedings of the National Academy of Sciences) 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. [10] 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. In other words, <6 hours of sleep predisposes people to chronic inflammation and tumor genesis or inflam-aging.

Some of the more interesting sleep associations I have found includes sexuality, productivity, and likeability. [11,12,13] If we want to be socially engaged, apparently allowing enough sleep is important. One of Dr. Walkers recent studies shows that sleep loss causes social withdrawal and loneliness. Sleep also seems to impact the brain’s ability to encode new information. This has broad implications, but it’s particularly important for students, or anyone wanting to learn new things such as new acquaintances’ names and the elderly, who are at risk for dementia. [14,15,16] 

Sleep is stigmatized as laziness, but from the studies I have read, adequate sleep can actually lead to a healthier, happier you.  Putting it together, sleep seems improve longevity through lowering the likelihood of disease, accidents and decrepitude. Most people need to allow at least 7 hours of sleep nightly. [17] It may be hard to find the time, but from a risk (loss of time) benefit (improved longevity, social engagement, cognitive performance) perspective, I feel the time investment is repaid by the significant benefits.

So you may ask how can I begin to give myself adequate sleep.  Dr. Walker suggests there are three key factors to maintaining a healthy sleep pattern:
1. Regularity: Maintain consistent sleep and rise times.  
2. Darkness: Try to limit screen time and dim home lights the hour before bed. Darkness is needed for melatonin secretion.
3. Cooler room temperatures: Turn down the heat. Your core body temperature is supposed to drop two to three degrees.

I interpret his three keys as ways to help maintain circadian rhythm, which is an internal clock that regulates our sleep/ wake cycle.  
*Blue light simulates morning light, which at night can hurt sleep. So, the timing of your blue light exposure is important. [15,16,17,18,19,20]

*Morning time outside gives your photoreceptors strong circadian cues. 

*In the evenings, research shows it is best to avoid all blue light (phone screens, computers, TVs), but if you need to work on your computers or phone considers using night shift on iPhones or f.lux that can adjust color based on location and time or you can even use the super cool (not really) blue blocking glasses.  [21,22,23,24,25]

*When you are ready for sleep, a quiet room is also important. You may want to consider noise blocking devices such as kokoon or if you have a noisy partner, there is always the “sleep divorce” as popularized recently by Carson Daly.

*There is evidence that meditation can improve sleep. Please see last weeks post for suggestion on meditation apps.  [26]

*Lastly. CBTI (Cognitive Behavioral therapy for insomnia) has shown great efficacy in improving sleep. [27] Apps such as CBTI coach (from the VA, Stanford SOM and the DoD) and Pzziz are both effective and well  researched.

That is it for this week.  Next week, we will talk about what the research really shows us on nutrition and longevity, and what steps you can take towards a healthier, happier you!



1. 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

2. 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

3. 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
4. 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.
5. 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. 

6. 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

7. 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 

8. Sheen et al. 1996. Relationships between sleep quality and glucose regulation in normal humans. American journal of physiology. 01 AUG 1996. https://doi.org/10.1152/ajpendo.1996.271.2.E261 

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

10. 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.

11. Cote et al 2013. Sleep deprivation lowers reactive aggression and testosterone in men. Biological Psychology. Volume 92, Issue 2, February 2013, Pages 249-256. https://doi.org/10.1016/j.biopsycho.2012.09.011

12. Ben Simon, E., Walker, M.P. 2018 Sleep loss causes social withdrawal and loneliness. Nat Commun 9, 3146 doi:10.1038/s41467-018-05377-0

13. Rosekind et al. 2010. The Cost of Poor Sleep: Workplace Productivity Loss and Associated Costs. Journal of Occupational and Environmental Medicine: January 2010 - Volume 52 - Issue 1 - p 91-98. doi: 10.1097/JOM.0b013e3181c78c30.

14. Walker MP. 2008. Sleep-dependent memory processing. Harv Rev Psychiatry. 16(5):287-98. doi: 10.1080/10673220802432517.

15.Walker, MP. 2008. Cognitive consequences of sleep and sleep loss . Sleep Medicine. Volume 9, Supplement 1, September 2008, Pages S29-S34

16. Mander et al. 2013. Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging. Nature Neuroscience,. Volume 16, pages 357–364.

17. NSF -https://www.sleepfoundation.org/articles/how-much-sleep-do-we-really-need

18. Shechter et al. 2017. Blocking nocturnal blue light for insomnia: A randomized controlled trial. Journal of Psychiatric Research. Volume 96, Pages 196-202. doi: 10.1016/j.jpsychires.2017.10.015
19. Zimmerman et al. 2019. Neuropsychological Function Response to Nocturnal Blue Light Blockage in Individuals With Symptoms of Insomnia: A Pilot Randomized Controlled Study, Journal of the International Neuropsychological Society, Volume 25, Issue 7, pp. 668-677. 
20. Czeisler CA (2013) Perspective: Casting light on sleep deficiency. Nature 497(7450):S13

21. Cajochen et al. 2011. Evening exposure to a light-emitting diodes (LED)-backlit computer screen affects circadian physiology and cognitive performance. Journal of Applied Physiology. 110(5):1432-8. doi: 10.1152/japplphysiol.00165.2011.
22. Czeisler et al. 2015. Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness. PNAS- Proceedings of the National Academy of Sciences of the United States of America. 112 (4) 1232-1237;
23. Lockley et al. 2003.  High Sensitivity of the Human Circadian Melatonin Rhythm to Resetting by Short Wavelength Light. The Journal of Clinical Endocrinology & Metabolism, Volume 88, Issue 9, Pages 4502–4505, https://doi.org/10.1210/jc.2003-030570

24.Burkhart et al. 2009 Amber lenses to block blue light and improve sleep: a randomized trial. Chronobiol Int. 2009 Dec;26(8):1602-12. doi: 10.3109/07420520903523719.
25. Van der Lely, S et al. 2015. Blue blocker glasses as a countermeasure for alerting effects of evening light-emitting diode screen exposure in male teenagers. J Adolesc Health. 56(1):113-9. doi: 10.1016/j.jadohealth.2014.08.002

26. Black, D et al. 2015. Mindfulness Meditation and Improvement in Sleep Quality and Daytime Impairment Among Older Adults With Sleep Disturbances A Randomized Clinical Trial. JAMA Internal Medicine. 175(4):494-501. doi:10.1001/jamainternmed.2014.8081

27. Jacobs et al. 2004. Cognitive behavior therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct comparison.  Arch Intern Med. 2004 Sep 27;164(17):1888-96.

#2 Can Mindfulness Improve Longevity?

11/2/2019

 
Picture
This week, we are talking about  what the research really shows on living better, longer and mindfulness.  This is the second part of a four part series on how to play hard, work hard, and be fully engaged with family, friends and community for as long as possible.

I have read many claims of improved aging with mindfulness but wanted to see the data myself, so I took a deep dive into the literature of mindfulness and this is what I found.

As you  probably know, mindfulness can take many forms. Mindfulness is a catch-all  term,  but what I think is at the heart of mindfulness is taking time out, whether through meditation, prayer or simply alone time. The blue zones research has shown most centenarians practiced some form of mindfulness, and research shows that in any form, the simple act of taking time out allows for stress reduction. [1,2]​

Since most of the mindfulness research has been done on meditation, I will focus on that today. 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). [3,4]  When our sympathetic nervous system is over activated for days, weeks or months we experience more stress and our bodies experience more inflammation. [5]

This implies that if we increase our parasympathetic tone we can improve on our ability to heal, and if we heal better, we will age better. [6] This is exactly what some studies have shown.  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. [2] 

The benefits of meditations have also been evaluated by prominent researchers like Clifford Saron of UC Davis and Nobel Prize winner Elizabeth Blackburn.  They evaluated aging through the lens of stress hormones and DNA (telomere length).  Telomeres protect your DNA. They are protective caps at the ends of chromosomes.  As people age, telomeres shorten. Chronic stress has also been associated with faster telomere shortening, but the catch 22 is that as telomeres shorten people age more rapidly.  Short telomeres have been linked to minor inconveniences like wrinkles and gray hair as well as larger issues like alzhiemer’s, some cancers and heart disease. 

Dr. Blackburn has evaluated the effect of meditation on both stress levels and telomere length and found meditation is associated with longer telomere length. A summary of her work published in 2011 states, “Given the pattern of associations… meditation may have salutary effects on telomere length`…”[7] In other words, meditation seems to help maintain telomere length. 

Dr. Saron of UC-Davis has also shown that meditation is associated with a lower level of the stress hormone cortisol and increased activity of telomerase (the enzyme that can lengthen telomeres). [8].  His studies have also shown that meditation may improve working memory and DHEA levels.  DHEA is a hormone that declines with age and is associated with improved cognitive performance. 

From a risk-benefit perspective and given improvements seen in cognitive performance, aging and healing, I suggest a daily mindfulness practice to all of my patients. If you are a mindfulness novice, there are a few easy ways to begin. 


  • 4-7-8 breaths helps to lower stress levels. To perform a 4-7-8 breath you inhale for a count of 4, hold for a count of 7 and exhale for a count of 8.   Dr. Andrew Weill, a father of integrative medicine also uses it to bring on sleep more quickly. 
 
  • Download one of the many apps available that teach mindfulness and meditation. Calm and Headspace are two of the more popular choices.
 
  • Try Waking Up, one of my new favorite apps that teaches mindfulness. Unlike many other mindfulness practices that “present meditation like an ancient executive stress ball… Waking up has the goal of allowing you to discover in the laboratory of your own mind.”

That is it for this week.  Next week, we will talk about what the research really shows us on sleep!

1.Buettner, D. (2012) The Blue Zones: 9 lessons for living longer from the people who've lived the longest (2nd ed.). Washington, D.C. National Geographic.

2. 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
​

3. 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

4. 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

5. 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

6.Fountain-Zaragoza, S. Prakash, R. S. (2017) Mindfulness Training for Healthy Aging: Impact on Attention, Well-Being, and Inflammation. Front Aging Neurosci. 9: 11. Published online 2017 Feb 3. doi: 10.3389/fnagi.2017.00011

7. Epel, E., Daubenmier, J., Moskowitz, J.T., Folkman, S., Blackburn, E. (2009) Can meditation slow rate of cellular aging? Cognitive stress, mindfulness, and telomeres.  Ann N Y Acad Sci. doi: 10.1111/j.1749-6632.2009.04414.x

8.Conklin, Q. A., King, B. G., Zanesco, A. P., Lin, J., Hamidi, A. B., Pokorny, J. J., Saron, C. D. (2018). Insight meditation and telomere biology: The effects of intensive retreat and the moderating role of personality. Brain, Behavior, and Immunity, 70, 233–245. 
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