Unconventional Longevity

What might be a functional medicine approach to extending the "healthspan?"

Dr. Peter Attia, well-known to people interested in cutting edge science related to longevity, recently published his first book, Outlive, now a non-fiction New York Times best seller. The book is receiving mostly high praise on Amazon and Good Reads.
At this point, most people know the basics of longevity:

• eat your vegetables
• exercise regularly
  
• treat known conditions
• do preventative testing
• don’t smoke

We also understand that we want to live not only longer, but also be as healthy as possible hopefully until the end.
Conventional medicine has long taught that there are actionable ways to avoid an early death. Public health has supported “health promotion and disease prevention,” and sets periodic goals for individual preventive services. The US Preventive Services Task Force publishes guidelines after reviewing the latest evidence. A service needs not only to be effective in reducing the harm from a certain disease, it also needs to not cause significant additional harm.


Medicine 3.0

I admit I have not read Outlive, but I have been a faithful listener of 250 or more of Attia's podcasts, since the first one came out in 2018. I am very familiar with his outlook and recommendations.
Attia introduces the concept of “Medicine 3.0.” The idea is that Medicine 1.0 is what happened when we found effective treatments for acute illnesses. Medicine 2.0, which is what most doctors are practicing, addresses chronic illness with certain medications. It also recommends certain diets (for example, the DASH diet for hypertension), and admits that sufficient exercise, stress reduction, and sleep are relevant to avoiding and managing chronic conditions. By Attia’s definition, Medicine 3.0 would build on its precursor by integrating advances in technology, data analytics, and systems biology to deliver truly personalized and precision medicine. Medicine 3.0 would leverage digital health technologies, artificial intelligence, and predictive analytics to optimize health outcomes and enable earlier detection and intervention. Under this banner, Attia also promotes the concept of “healthspan" extension, aiming to prolong healthy and functional life by targeting the underlying mechanisms of aging and age-related diseases.

Interestingly I don’t think this type of medicine is available, many of the tests may be used in research settings but not in clinical settings, and only a few people can afford all the high tech tools, some of which have no proven net benefit. Accordingly, the most common critique of Outlive appears to be that it fails to give practical information.

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​Functional Medicine and the Healthspan

Attia is not trained in functional medicine, and what he recommends overlaps with but does not encompass all of functional medicine. For example, I have never heard him or any of his podcast guests mention that an “elimination diet” meant to improve the quality and quantity of gut bacteria can powerfully impact cholesterol, including his favorite metric, the apolipoprotein B. But I have observed this repeatedly in my practice. It is almost a surprise when it doesn’t happen. To be fair, there does not appear to be research on this, but I learned it from my teachers in functional medicine.

So as I scanned the several hundred reviews of Attia’s book, I wondered how the functional medicine approach to longevity and the health span would be different. The only study of longevity (actually using the Horvath clock as a proxy for longevity) showed that a specific diet (“Younger You”) resulted in the subjects becoming 3 years younger on average, after an 8-week diet change (Fitzgerald et al, 2021).

Functional medicine has called itself “21st Century Medicine.” The emphasis on lifestyle, systems biology, and abundant lab work is present in both functional medicine and Medicine 3.0.

However, functional medicine also emphasizes the following, and Attia fails to do so, in spite of the fact that there is reasonable evidence for their importance:

1. Environmental toxins are playing a significant role in ill health, and this is gaining mainstream recognition (Lamas et al, 2023). We are exposed to neurotoxins, immunotoxins, endocrine disruptors, and carcinogenic substances. These need attention.
2. Many people have inadequate nutrients. While conventional medicine focuses on a few (B12, iron, sometimes vitamin D), and Attia mentions folate and magnesium, we have good evidence for the importance of optimizing several others, including omega 3s, zinc, copper, calcium, coenzyme Q10, and DHEA (see references)
3. We can improve gut bacteria and biomes throughout the body; there is definitely enough actionable clinical research on this (Wastyk et al, 2021)
4. We can and should improve intestinal permeability; I don’t remember Attia ever discussing “leaky gut” though it is understood to be a cornerstone problem (Fukui, 2016)
5. We need to look for and target common persistent infections: for example Herpes simplex 1 (cause of cold sores) is related to Alzheimer’s disease, and treating with antivirals when appropriate likely reduces the risk of dementia (Lopatko Lindman et al, 2021)

A practical proposal

So I would like to propose Medicine 2.5/Functional Longevity: something that uses the science we have, and the tools that are presently available to us, to design a root-cause, personalized approach to longevity and healthspan:

1. Start with a complete patient history
2. Add US Preventive Services Task Force recommended testing (mammography, colonoscopy, and more depending on age and sex and risk factors)
3. Add basic blood testing that insurance normally covers, as justified by pre-existing conditions
4. Add self-pay testing, depending on interest and level of evidence, including: levels of certain key nutrients, blood and urine heavy metal levels, levels of antibodies to certain common infections that might tell us whether they are still too active, and other actionable markers
5. Consider microbiome testing: it is in development, but it is an option that can be explored. At any rate, some of the research-proven ways of improving the microbiome can be undertaken even without testing.
6. Use available Medicine 3.0 tools, like the continuous glucose monitor, body composition DEXA scan, and the continuous monitor for heart rate variability, to gain insight into these important parameters
7. Individualize diet recommendations
8. Learn stress reduction tools: heart rate variability (HRV), a marker of stress, is related to many diseases and to survival itself. So we should be well-versed in ways to improve HRV. We have an option for continuous HRV measurement.
9. Use low tech interventions optimally: overnight fasting is one such intervention. Attia does not recommend fasting for longer than 14 hours due to possible muscle loss. That is definitely something that can be individualized. Another is the fasting-mimicking diet: a tool for improving cholesterol levels, insulin resistance, and overall, favorably altering the microbiome to improve symptoms of various autoimmune diseases, and also response to chemotherapy (Longo et al, 2021)
10. Individualize exercise. Attia spends a lot of time exercising, including several hours weekly in Zone 2 training (moderate intensity steady-state cardio). On the other hand, Stacy Sims, PhD, an exercise researcher who specializes in women’s physiology, says that Zone 2 training is not so important for postmenopausal women, while other types of exercise take on more importance. Too much exercise reliably brings on low heart rate variability, a risk factor for many diseases.
11. Pay close attention to additional systems biology approaches, such as sufficient stomach acid, to make sure the stomach can serve all the roles it specializes in; dental care, hearing testing, eye care — senses are an important part of keeping the brain cognitively healthy.

The Root-Cause Approach

When it comes to the core parameters of longevity, functional medicine takes more of a root-cause approach than I ever hear discussed in Attia podcasts. Or sometimes, an approach that leverages the body’s pre-existing pathways to health. Here are some key parameters to optimize when aiming for a longer healthspan, and how one would address them using a root-cause approach. None of these work for everyone, and some should only be attempted after other steps have been taken.

1. Blood pressure: diet, exercise, elimination diet, stretching, nitric oxide supplements — and of course medication if all else fails. Treated hypertensives are never as healthy as normotensive people
2. High LDL or high apolipoprotein B: diet, exercise, fasting-mimicking diet, elimination diet, fiber, consider the impact of saturated fat, or the impact of carbohydrates
3. Homocysteine: B vitamins, elimination diet, omega 3 supplements
4. Glucose and insulin/insulin resistance diet, exercise, sleep, elimination diet, fasting-mimicking diet, stress reduction, improving HRV, increasing plant-based foods, ketogenic diet — it really depends on the person
5. VO2 Max: coenzyme Q10 and other mitochondrial nutrients, exercise
6. Bone health: calcium, vitamin D, exercise, diet, sleep, homocysteine, gluten-sensitivity, leaky gut and inflammation
7. Colon health: optimize gut bacteria, diet, exercise, elimination diet, probiotics, fermented foods, fiber (but in what order? That is dependent on the individual)
8. Muscle mass: exercise, diet (enough protein), reducing inflammation, sleep
9. Improving sleep: monitoring HRV, supplementation, making practical changes to sleeping environment and to preparation for sleep
10. Overweight: fasting-mimicking diet, 13-14 hour overnight fasting, elimination diet, exercise, toxins
11. CPR and other markers of inflammation: elimination diet, probiotics, sleep, stress reduction, exercise, cur cumin or anti-inflammatory herbs.

MORE DETAILS ON OUR UNCONVENTIONAL LONGEVITY PROGRAM HERE.
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REFERENCES
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https://pubmed.ncbi.nlm.nih.gov/33844651/
Fitzgerald KN, Hodges R, Hanes D, Stack E, Cheishvili D, Szyf M, Henkel J, Twedt MW, Giannopoulou D, Herdell J, Logan S, Bradley R. Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial. Aging (Albany NY). 2021 Apr 12;13(7):9419-9432. doi: 10.18632/aging.202913. Epub 2021 Apr 12. Erratum in: Aging (Albany NY). 2022 Jul 27;14(14):5959. PMID: 33844651; PMCID: PMC8064200.

https://pubmed.ncbi.nlm.nih.gov/29922669/
Fukui H. Increased Intestinal Permeability and Decreased Barrier Function: Does It Really Influence the Risk of Inflammation? Inflamm Intest Dis. 2016 Oct;1(3):135-145. doi: 10.1159/000447252. Epub 2016 Jul 20. PMID: 29922669; PMCID: PMC5988153.

https://pubmed.ncbi.nlm.nih.gov/37306302/
Lamas GA, Bhatnagar A, Jones MR, Mann KK, Nasir K, Tellez-Plaza M, Ujueta F, Navas-Acien A; American Heart Association Council on Epidemiology and Prevention; Council on Cardiovascular and Stroke Nursing; Council on Lifestyle and Cardiometabolic Health; Council on Peripheral Vascular Disease; and Council on the Kidney in Cardiovascular Disease. Contaminant Metals as Cardiovascular Risk Factors: A Scientific Statement From the American Heart Association. J Am Heart Assoc. 2023 Jul 4;12(13):e029852. doi: 10.1161/JAHA.123.029852. Epub 2023 Jun 12. PMID: 37306302.

https://pubmed.ncbi.nlm.nih.gov/35310455/
Longo VD, Di Tano M, Mattson MP, Guidi N. Intermittent and periodic fasting, longevity and disease. Nat Aging. 2021 Jan;1(1):47-59. doi: 10.1038/s43587-020-00013-3. Epub 2021 Jan 14. PMID: 35310455; PMCID: PMC8932957.

https://pubmed.ncbi.nlm.nih.gov/33614892/
Lopatko Lindman K, Hemmingsson ES, Weidung B, Brännström J, Josefsson M, Olsson J, Elgh F, Nordström P, Lövheim H. Herpesvirus infections, antiviral treatment, and the risk of dementia-a registry-based cohort study in Sweden. Alzheimers Dement (N Y). 2021 Feb 14;7(1):e12119. doi: 10.1002/trc2.12119. PMID: 33614892; PMCID: PMC7882534.

https://pubmed.ncbi.nlm.nih.gov/34256014/
Wastyk HC, Fragiadakis GK, Perelman D, Dahan D, Merrill BD, Yu FB, Topf M, Gonzalez CG, Van Treuren W, Han S, Robinson JL, Elias JE, Sonnenburg ED, Gardner CD, Sonnenburg JL. Gut-microbiota-targeted diets modulate human immune status. Cell. 2021 Aug 5;184(16):4137-4153.e14. doi: 10.1016/j.cell.2021.06.019. Epub 2021 Jul 12. PMID: 34256014; PMCID: PMC9020749.


General Nutrients
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138658/
Quan Z, Li H, Quan Z, Qing H. Appropriate Macronutrients or Mineral Elements Are Beneficial to Improve Depression and Reduce the Risk of Depression. Int J Mol Sci. 2023 Apr 12;24(8):7098. doi: 10.3390/ijms24087098. PMID: 37108261; PMCID: PMC10138658.


Specific Nutrients
Omega 3s
https://pubmed.ncbi.nlm.nih.gov/36795219/
von Schacky C, Kuipers RS, Pijl H, Muskiet FAJ, Grobbee DE. Omega-3 fatty acids in heart disease-why accurately measured levels matter. Neth Heart J. 2023 Feb 16. doi: 10.1007/s12471-023-01759-2. Epub ahead of print. PMID: 36795219.


Zinc
https://pubmed.ncbi.nlm.nih.gov/32258830/
Qu X, Yang H, Yu Z, Jia B, Qiao H, Zheng Y, Dai K. Serum zinc levels and multiple health outcomes: Implications for zinc-based biomaterials. Bioact Mater. 2020 Mar 31;5(2):410-422. doi: 10.1016/j.bioactmat.2020.03.006. PMID: 32258830; PMCID: PMC7114479.


DHEA
https://pubmed.ncbi.nlm.nih.gov/32745490/
Wang F, He Y, O Santos H, Sathian B, C Price J, Diao J. The effects of dehydroepiandrosterone (DHEA) supplementation on body composition and blood pressure: A meta-analysis of randomized clinical trials. Steroids. 2020 Nov;163:108710. doi: 10.1016/j.steroids.2020.108710. Epub 2020 Jul 31. PMID: 32745490.


https://pubmed.ncbi.nlm.nih.gov/33220453/
Hu Y, Wan P, An X, Jiang G. Impact of dehydroepiandrosterone (DHEA) supplementation on testosterone concentrations and BMI in elderly women: A meta-analysis of randomized controlled trials. Complement Ther Med. 2021 Jan;56:102620. doi: 10.1016/j.ctim.2020.102620. Epub 2020 Nov 18. PMID: 33220453.


Copper
https://pubmed.ncbi.nlm.nih.gov/21321490/
Prodan CI, Rabadi M, Vincent AS, Cowan LD. Copper supplementation improves functional activities of daily living in adults with copper deficiency. J Clin Neuromuscul Dis. 2011 Mar;12(3):122-8. doi: 10.1097/CND.0b013e3181dc34c0. PMID: 21321490.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9554529/
Klevay LM. The contemporaneous epidemic of chronic, copper deficiency. J Nutr Sci. 2022 Oct 11;11:e89. doi: 10.1017/jns.2022.83. PMID: 36304823; PMCID: PMC9554529.


Pregnenolone
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200497/
Brown ES, Park J, Marx CE, Hynan LS, Gardner C, Davila D, Nakamura A, Sunderajan P, Lo A, Holmes T. A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology. 2014 Nov;39(12):2867-73. doi: 10.1038/npp.2014.138. Epub 2014 Jun 11. PMID: 24917198; PMCID: PMC4200497.


https://pubmed.ncbi.nlm.nih.gov/32119096/
Naylor JC, Kilts JD, Shampine LJ, Parke GJ, Wagner HR, Szabo ST, Smith KD, Allen TB, Telford-Marx EG, Dunn CE, Cuffe BT, O'Loughlin SH, Marx CE. Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain Among US Military Veterans: A Randomized Clinical Trial. JAMA Netw Open. 2020 Mar 2;3(3):e200287. doi: 10.1001/jamanetworkopen.2020.0287. PMID: 32119096; PMCID: PMC7052727.


Magnesium
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637834/
Schwalfenberg GK, Genuis SJ. The Importance of Magnesium in Clinical Healthcare. Scientifica (Cairo). 2017;2017:4179326. doi: 10.1155/2017/4179326. Epub 2017 Sep 28. PMID: 29093983; PMCID: PMC5637834.