Tag: agiing

Notes from “How Not to Age” Part 1 — Presentation by Dr. Michael Greger

I watched a YouTube presentation by Dr. Greger that introduces his new book “How Not to Age” and decided I would make a few notes. The book will be released on 5 December 2023 and I plan to read it. One thing led to another and now I have a pretty detailed set of notes on this presentation that I think might be useful to others. This is part 1 of a series of posts, it covers the first 21 minutes of the talk. If there are errors in this post, they are likely mine, let me know and I will correct it. I learned a couple of things from this talk:
1. increase my intake of foods that contain spermidine; I am adding wheat germ to my diet every day.
2. Investigate fasting to increase autophagy [11]
3. When possible, try to exercise for 60 minutes or longer [13]
4. Can’t wait to read the book but I also wanted to read a few of the papers.

I researched the citations to some of the papers that Dr. Greger cites in the talk. One reason I did this is to keep up with the sheer volume of research that he uses in the talk; he covers a lot of ground. It was interesting to see that some of the papers cited in his talk aren’t included in “How Not to Age”.

Notes for Part 1

  • Centenarians die of disease; not old age
  • Aging kills via disease, why wasn’t “How Not to Die” a good enough book?
    • BUT rate of death increases exponentially as we age
      • Risk doubles about every 7 years
    • Age is the leading risk factor for disease
    • Cholesterol is a modifiable risk factor
    • What if the rate of aging was modifiable? 
  • Slowing down the rate of aging would address risk from many diseases.
  • Anti-aging schemes unscrupulous (at best)
  • Need to rely on evidence, not anecdotes
  • “My aim was to cover every possible angle for developing the optimal diet and lifestyle for the longest, healthiest lifespan based on the best available balance of evidence.” Dr. Greger’s goal
    • Experts such as Valter Longo and David Sinclair have identified essential pathways that can be modified by drugs [1]
    • Dr. Greger realized these eleven pathways can be modified via diet
  • Part 1“Slowing Aging by Blocking Eleven Pathways to Aging”
    • The phrase “anti-aging” is greatly abused in popular culture, often for the purpose of marketing cosmetic procedures or unproven nutritional supplements purported to slow or reverse aging. This has the unfortunate consequence of creating confusion among the general public and diminishing the impact of legitimate scientific discovery. Here, we define “anti-aging” as delaying or reversing biological aging by targeting the established molecular mechanisms of aging, which have been formalized as “hallmarks” or “pillars” of aging. [2]

 Hallmarks of Aging 

The Hallmarks of Aging
Figure 1. The Hallmarks of Aging The scheme enumerates the nine hallmarks described in this review: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial, dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. [3]
  • [7:30] Autophagy “Self-eating” housekeeping process by which defective cellular components are scrapped for spare parts clearing out damage implicated in aging process
    • Autophagy, a term acquired from the Greek words “auto (self)” and “phagein (to eat)”, literally meaning “self-eating”, refers to an evolutionary conserved catabolic mechanism that allows cells to remove their own unnecessary or dysfunctional components.[4]
  • Autophagy critical for lifespan and healthspan extension
    • Proteostasis is supported by autophagy, a conserved machinery that helps to eliminate dysfunctional proteins and cellular organelles via lysosomal degradation. The rejuvenating power of cleaning up garbage and replacing it with recycled and newly synthesized cellular components speaks to the imagination and is an attractive explanation for the positive correlation between autophagy and lifespan.[5]
    • …. mounting evidence suggesting that autophagy is not only necessary but, at least in some cases, also sufficient for increasing longevity.[6]
    • …. specific activation of autophagy through a mutation in beclin 1 prolongs median survival by approximately 12% in both male and female mice. [7]
    • A decrease in autophagy with age has been described in almost all organisms and tissues analyzed.[8]
  • Pharma wants to exploit autophagy using drugs
    • To circumvent such diseases of aging, efforts to pharmacologically modulate autophagy are at the forefront of multiple research programs in academia and the pharmaceutical industry.[9]
  • Fasting can cause autophagy [10]
    • Don’t fast longer than 24 hours without medical help
    • Fasting periods lasting longer than 24 hours and particularly those lasting 3 or more days should be done under the supervision of a physician and preferably in a clinic.[11]
  • Exercise can cause autophagy [12]
    • Activated after more than 60 minutes of moderate exercise
      These data demonstrate that autophagy signaling is activated in human skeletal muscle after 60 min of exercise, independently of nutritional status, and suggest that initiation of autophagy constitutes an important physiological response to exercise in humans.[13]
  • Diet can inhibit autophagy
    • Acrylamide – in deep fried foods (fries, chips) causes inflammation [14][15]
    • Put it to the test – some evidence
    • Air frying is better [16]
  • Coffee (including decaf) can activate autophagy [17]
    • Bioactive compounds other than caffeine
      • Chlorogenic acids (CGA)
  • Spermidine rich foods activate autophagy[18]
    • Levels decline with age (except in naked mole rats which don’t age [19])
    • Largest documented lifespan extension [20]
    • Improves cardiac, [21] immune, [22] and brain function in animals
    • In humans, greatest consumption of spermidine has lowest mortality[24]
    • An anti-aging vitamin to maintain autophagy
      In sum, in our view, spermidine is synthesized by our organism in sufficient quantities during youth, but not in old age. Thus, one may argue that, as we age, spermidine evolves to the status of a vitamin, and thus has to be supplemented from external sources to secure the maintenance of autophagic flux required for organismal homeostasis. [25]
Top Spermidine Sources
[18:34] Top Spermidine Sources [24]
  • Wheat germ is the most concentrated source of spermidine, 2.5 mg per tablespoon
  • Caused improvement in mild dementia patients
  • Work much better than Aducanumab anti-Alzheimer drug
  • Autophagy Takeaways (summary from “How Not to Age”)[26]
    To help slow this aging pathway, on a daily basis, consider.
    • 60 min or more of moderate to vigorous (55%-70% VO2 max) aerobic exercise
    • minimizing your intake of french fries and potato chips
    • drinking three cups of regular or decaffeinated coffee
    • trying to consume at least 20 mg of spermidine by incorporating foods such as tempeh, mushrooms, peas, and wheat germ into your diet
    • instituting the recommendations to activate AMPK (see chapter 1)
    • following the recommendations to suppress mTOR (see chapter 8) “How Not to Age”  diet and lifestyle takeaways for 10 other aging pathways

References

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  • [13] Møller AB, Vendelbo MH, Christensen B, Clasen BF, Bak AM, Jørgensen JO, Møller N, Jessen N. Physical exercise increases autophagic signaling through ULK1 in human skeletal muscle. J Appl Physiol (1985). 2015 Apr 15;118(8):971-9. doi: 10.1152/japplphysiol.01116.2014. Epub 2015 Feb 12. PMID: 25678702. https://journals.physiology.org/doi/10.1152/japplphysiol.01116.2014 Not referenced in How Not to Age Citations
  • [14] Song D, Xu C, Holck AL, Liu R. Acrylamide inhibits autophagy, induces apoptosis and alters cellular metabolic profiles. Ecotoxicol Environ Saf. 2021 Jan 15;208:111543. doi: 10.1016/j.ecoenv.2020.111543. Epub 2020 Nov 9. PMID: 33396091. https://www.sciencedirect.com/science/article/pii/S0147651320313804 Cited as reference 253 in How Not to Age Citations
  • [15] Naruszewicz M, Zapolska-Downar D, Kośmider A, Nowicka G, Kozłowska-Wojciechowska M, Vikström AS, Törnqvist M. Chronic intake of potato chips in humans increases the production of reactive oxygen radicals by leukocytes and increases plasma C-reactive protein: a pilot study. Am J Clin Nutr. 2009 Mar;89(3):773-7. doi: 10.3945/ajcn.2008.26647. Epub 2009 Jan 21. Erratum in: Am J Clin Nutr. 2009 Jun;89(6):1951. PMID: 19158207. https://linkinghub.elsevier.com/retrieve/pii/S0002-9165(23)23747-8 Cited as reference 253 in How Not to Age Citations
  • [16] Sansano M, Juan-Borrás M, Escriche I, Andrés A, Heredia A. Effect of pretreatments and air-frying, a novel technology, on acrylamide generation in fried potatoes. J Food Sci. 2015 May;80(5):T1120-8. doi: 10.1111/1750-3841.12843. Epub 2015 Apr 13. PMID: 25872656. Not referenced in How Not to Age Citations
  • [17] Pietrocola F, Malik SA, Mariño G, Vacchelli E, Senovilla L, Chaba K, Niso-Santano M, Maiuri MC, Madeo F, Kroemer G. Coffee induces autophagy in vivo. Cell Cycle. 2014;13(12):1987-94. doi: 10.4161/cc.28929. Epub 2014 Apr 25. PMID: 24769862; PMCID: PMC4111762. Cited as reference 255 in How Not to Age Citations
  • [18] Madeo F, Eisenberg T, Büttner S, Ruckenstuhl C, Kroemer G. Spermidine: a novel autophagy inducer and longevity elixir. Autophagy. 2010 Jan;6(1):160-2. doi: 10.4161/auto.6.1.10600. PMID: 20110777. Not referenced in How Not to Age Citations
  • [19] Viltard M, Durand S, Pérez-Lanzón M, Aprahamian F, Lefevre D, Leroy C, Madeo F, Kroemer G, Friedlander G. The metabolomic signature of extreme longevity: naked mole rats versus mice. Aging (Albany NY). 2019 Jul 24;11(14):4783-4800. doi: 10.18632/aging.102116. PMID: 31346149; PMCID: PMC6682510. Cited as reference 323 in How Not to Age Citations
  • [20] Eisenberg T, Knauer H, Schauer A, Büttner S, Ruckenstuhl C, Carmona-Gutierrez D, Ring J, Schroeder S, Magnes C, Antonacci L, Fussi H, Deszcz L, Hartl R, Schraml E, Criollo A, Megalou E, Weiskopf D, Laun P, Heeren G, Breitenbach M, Grubeck-Loebenstein B, Herker E, Fahrenkrog B, Fröhlich KU, Sinner F, Tavernarakis N, Minois N, Kroemer G, Madeo F. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009 Nov;11(11):1305-14. doi: 10.1038/ncb1975. Epub 2009 Oct 4. PMID: 19801973. Cited as reference 319 in How Not to Age Citations
  • [21] Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, Harger A, Schipke J, Zimmermann A, Schmidt A, Tong M, Ruckenstuhl C, Dammbrueck C, Gross AS, Herbst V, Magnes C, Trausinger G, Narath S, Meinitzer A, Hu Z, Kirsch A, Eller K, Carmona-Gutierrez D, Büttner S, Pietrocola F, Knittelfelder O, Schrepfer E, Rockenfeller P, Simonini C, Rahn A, Horsch M, Moreth K, Beckers J, Fuchs H, Gailus-Durner V, Neff F, Janik D, Rathkolb B, Rozman J, de Angelis MH, Moustafa T, Haemmerle G, Mayr M, Willeit P, von Frieling-Salewsky M, Pieske B, Scorrano L, Pieber T, Pechlaner R, Willeit J, Sigrist SJ, Linke WA, Mühlfeld C, Sadoshima J, Dengjel J, Kiechl S, Kroemer G, Sedej S, Madeo F. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016 Dec;22(12):1428-1438. doi: 10.1038/nm.4222. Epub 2016 Nov 14. PMID: 27841876; PMCID: PMC5806691 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806691/ Cited as references 325, 327. 336, 338 and 402 in How Not to Age Citations
  • [22] Castoldi F, Kroemer G, Pietrocola F. Spermidine rejuvenates T lymphocytes and restores anticancer immunosurveillance in aged mice. Oncoimmunology. 2022 Nov 14;11(1):2146855. doi: 10.1080/2162402X.2022.2146855. PMID: 36387057; PMCID: PMC9665084.Not referenced in How Not to Age Citations
  • [23] Schroeder S, Hofer SJ, Zimmermann A, Pechlaner R, Dammbrueck C, Pendl T, Marcello GM, Pogatschnigg V, Bergmann M, Müller M, Gschiel V, Ristic S, Tadic J, Iwata K, Richter G, Farzi A, Üçal M, Schäfer U, Poglitsch M, Royer P, Mekis R, Agreiter M, Tölle RC, Sótonyi P, Willeit J, Mairhofer B, Niederkofler H, Pallhuber I, Rungger G, Tilg H, Defrancesco M, Marksteiner J, Sinner F, Magnes C, Pieber TR, Holzer P, Kroemer G, Carmona-Gutierrez D, Scorrano L, Dengjel J, Madl T, Sedej S, Sigrist SJ, Rácz B, Kiechl S, Eisenberg T, Madeo F. Dietary spermidine improves cognitive function. Cell Rep. 2021 Apr 13;35(2):108985. doi: 10.1016/j.celrep.2021.108985. PMID: 33852843. https://linkinghub.elsevier.com/retrieve/pii/S2211-1247(21)00299-0 Not referenced in How Not to Age Citations
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  • [25] Madeo F, Bauer MA, Carmona-Gutierrez D, Kroemer G. Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans? Autophagy. 2019 Jan;15(1):165-168. doi: 10.1080/15548627.2018.1530929. Epub 2018 Oct 11. PMID: 30306826; PMCID: PMC6287690. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287690/ Cited as references 311 and 342 in How Not to Age Citations
  • [26] Greger, M. (2023). How Not to Age: The Scientific Approach to Getting Healthier As You Get Older.

Book review of Outlive: The Science and Art of Longevity by Peter Attia

Let me begin my review in the middle of Outlive. The author  asks us to list the ten tasks we want to do for the rest of our lives. He calls this list the centenarian decathlon. Here’s the top of the list for me: hike up to Third Burroughs Mountain. It’s 9 miles (14 km) in Mount Rainier National Park with 2500 feet (760 m.) of elevation gain. Why? I’m a hiker, and this is my favorite hike worldwide.

Up at Third Burroughs
Early morning at Third Burroughs 2003

I’ve spent a fair amount of time thinking about how to keep hiking as I get older. I turned 65 in 2022; I would like to keep exploring mountains as long as possible, this is just the book to help me achieve my goal. Let me explain why.

First, Attia starts with the concept of healthspan – how well you live. There’s a tight coupling between healthspan and lifespan. As we age, we have left less of each. One difference is that lifespan is a discrete quantity; one day, you are alive, and the next, you are not. In contrast, our healthspan gradually diminishes over time. The author details three vectors (components) of healthspan: physical, cognitive, and emotional. The good news is that we can usually improve these components and our overall healthspan. How we do so is the core of the book.

The book’s first part outlines our current situation and a target goal. The most important lesson I learned: “Tactics without strategy is the noise before defeat.” a quote from Sun Tzu, an ancient Chinese military strategist. Been there, done that, got the T-shirt. So, how can I do better? The author has a great framework: first, objectives, then strategy, and finally, tactics. The author trained as an engineer, became a physician, and has worked in business consulting; his background shows throughout the book. I touched on objectives in the discussion of the centenarian decathlon; how about strategy?

The second part of Outlive is the science that can help you develop a strategy. There is a chapter on the science of centenarians; I think of this as a boundary condition. What are the factors that helped get someone to their 100th birthday? (I have a hiking friend who still gets out on walks at 101, I want to follow in her footsteps.) Next is a chapter on the details of how nutrition affects longevity. The last four chapters cover the science of how most of us die: metabolic disorders such as diabetes, heart disease, cancer, and neurodegenerative diseases. Understanding these problems will help you develop tactics to mitigate some issues. There are no magic bullets in these chapters; instead, it’s a well-researched survey of what we know as of 2022. Now that we know objectives and strategies, what tactics can we employ?

The final part of Outlive lays out four tactics: 

  1. Exercise (cardio, strength, and stability)
  2. Nutrition
  3. Sleep 
  4. Emotional health.  

At 260 pages, this is the longest part of the book. It was detailed and beneficial to me. Rather than outline each section, let me list some tactics I am adding to my strategy: 

  1. Work on stability, specifically starting with a yoga class. 
  2. Use a continuous glucose monitor for a few months to optimize my diet. 
  3. Ensure I am getting enough protein intake of lysine, leucine, and methionine.

The last chapter on emotional health was the most impactful in the book. Attia opens up to the reader about his emotional health through the lens of a patient rather than a physician. It touched me deeply; I had some trauma in my teen years when my mom died. Fifty years later, I realized I should address some of these issues rather than wall them off. 

Outlive is a book I will read several times. The book is challenging; I spent four weeks reading the book.

Reading Outlive in Utah
Reading in camp at Grand Staircase-Escalante National Monument, Utah

I made a ton of margin notes and back-of-the-book scrawling. There’s a lot to digest, and there are many references. For example, I want to read the paper Hallmarks of Aging by Carlos López-Otín and colleagues. This book catalyzed some great conversations with my friend Bill about healthspan. I will recommend Outlive to anyone interested in taking action to improve their healthspan.  

One closing thought; there’s a missing chapter in the book. I believe social interaction and engagement can improve healthspan’s cognitive and emotional components. My experience is that forty years of marriage have improved my emotional health. I decided to ask ChatGPT: What studies have shown that social interaction and engagement can improve cognitive function and reduce the risk of cognitive decline and dementia in older adults? Here’s the answer: 

“There have been several studies that have shown a positive correlation between social interaction and cognitive function in older adults. For example:

The Rush Memory and Aging Project: This study found that older adults who had higher levels of social activity experienced a slower rate of cognitive decline than those who were less socially active.

The MacArthur Study of Successful Aging: This study found that older adults who were more socially engaged were less likely to experience declines in cognitive function over time.

The Women’s Health Initiative Memory Study: This study found that women who reported higher levels of social engagement had a lower risk of developing cognitive impairment than those who were less socially engaged.

Overall, these studies suggest that social interaction and engagement can play an important role in maintaining cognitive function and reducing the risk of cognitive decline and dementia in older adults.”