Huberman Lab Podcast - “Slowing & Reversing Aging"

Dr. David Sinclair: The Biology of Slowing & Reversing Aging

Podcast Host: Dr. Andrew Huberman (Stanford Associate Professor - brain development, brain plasticity, and neural regeneration and repair fields)
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- Lab Website
Podcast Guest: Dr. David Sinclair (Professor of Genetics at Harvard Medical School)
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Overview and Purpose:

Aging affects dynamic biological, physiological, environmental, psychological, behavioral, and social systems. These changes might happen at any age. Grey hair is typical with age. Others impair senses and everyday life and increase susceptibility to illness, frailty, and incapacity. Age is the main risk factor for many chronic diseases. Dr. Andrew Huberman asks Dr. David Sinclair questions on aging, longevity, the causes of aging, and a diet plan to combat aging, while Dr. David Sinclair answers his questions. The topics of discussion include aging, longevity, and the causes of aging. Dr. David Sinclair is considered an authority on the subject of aging due to his extensive study on the topic of aging, and he has personally experimented with a wide variety of anti-aging strategies. Even though he is over 50 years old, he has managed to get his biological age down to about 30, despite the fact that his real age is far above 50.

Dr. David Sinclair explains the causes of aging, which may include oxidative stress, glycation, telomere shortening, side reactions, mutations, protein aggregation, and telomere shortening are some of the factors that can contribute to aging. In addition to this, Dr. Sinclair provides in-depth information supported by studies on the nutritional influences on longevity.

Abbreviations: PCSK9: Pro-protein convertase subtilisin/kexin type 9; PCD: Programmed cell death eliminates specific cells in response to developmental or environmental stimuli; SIRT3: SIRT3 deacetylates and acetylates mitochondrial enzymes to regulate energy demand and metabolism during fasting and exercise; mTOR: mTOR regulates cell growth, autophagy, and death through various signaling pathways; AMPK: AMPK, an energy enzyme found in all mammalian cells, is phylogenetically conserved; NAD: NAD+ affects metabolic pathways, DNA repair, chromatin remodeling, cellular senescence, and immune cell activity; NMN: an enzyme, reduces age-related weight gain, improves energy metabolism and physical activity, insulin sensitivity, ocular function, mitochondrial metabolism, and gene expression; NR: NR is a precursor to the vital coenzyme NAD+; KRT1: The KRT1 gene makes keratin 1 protein; CRP: C-Reactive Protein binds to injured tissue, nuclear antigens, and pathogens. CRP is thought to function in the innate immune system.

Note: In the ethos of Open Science and transparent publication, this is a living document that will undergo continuous improvement. If you have suggestions, expansions, or corrections please feel free to comment in this thread and we will adjust the document as well as award some RSC for your help.

Discussion and Publications by Section

(1) 00:00:00 Dr. David Sinclair, Harvard Medical School

Dr. David Sinclair is a Professor of genetics at Harvard Medical School and also serves as a co-director of the Paul F. Glenn Center. The Paul F. Glenn Center is dedicated to the study of the biology of aging and Dr. Sinclair's research focuses on the question, "Why do we age?" and "How can we stop aging?" In addition, Professor David investigates the molecular pathways that are associated with aging. Dr. Sinclair has discovered several pathways inside the cell. In an effort to make people feel younger for longer, he investigates the effects of dietary and pharmaceutical interventions on people. Dr. Sinclair had a distinctive perspective on the aging process, both in people and in other animals. According to Dr. Sinclair, the natural and inevitable process of aging is not something that humans experience; rather, it is a disease. Dr. Sinclair is also the author of a book called "LifeSpan," which became a bestseller on The New York Times Best Seller List. The key discovery made by David was the identification of Sirtuins, which are components that have an effect on the Epigenome.

(2) 00:07:45 “Aging as a Disease” vs. Longevity & Anti-Aging

When it comes to doing a study on this subject, academic scientists most frequently make use of the phrase "longevity." Both "longevity" and "antiaging" refer to the same phenomenon, which is why they both have the same meaning: "to live for a very long time." Longevity, on the other hand, is a nice phrase to use when trying to describe this issue, and scientists typically use longevity. Anti-aging, on the other hand, is a term that is used by individuals who know nothing about the subject at all, and it is not a scientific word for discussing the subject. Currently, as a result of the discovery of several elements that are associated with aging, it is now considered to be a disease [1].

Professor Dr. David Sinclair of Harvard Medical School believes that aging is a disease. At the time of his research studies at Harvard Medical School, the definition of "disease" was as follows: "A disease is a rare condition that affects a person and must affect fewer than 50% of the population." Sinclair believes that aging is a disease. "Sometimes, a patient's life is ruined while attempting to find a cure for an illness," says Professor Dr. David Sinclair of the University of Edinburgh.

Cell turnover and tissue homeostasis need regulated apoptosis or necrosis. PCD mismanagement can cause senescence and illness. Certain highly mitotic tissues delay cell turnover with age. Aging-related systemic and intercellular communication issues, cell-autonomous damage, and mitochondrial failure enhance PCD in some cell types and decrease it in others. PCD increases with age, causing immune system weakness, sarcopenia, heart cell loss, and neurological illness. Cancer and senescent cells get older because they resist PCD. Fungi have a lifespan limited by the PCD pathways, although adult metazoans may not. Positive and negative variables like aging mitochondria regulate PCD. Aging causes various ailments, including Alzheimer's and heart disease. Professor David Sinclair believes 80-90% of Alzheimer's and heart disease are caused by aging. If the aging process stopped and the body stayed young, we wouldn't get all the ailments related to or caused by age. Professor Dr. David Sinclair works in his lab to reverse aging, hoping to cure all aging-related disorders and extend the lives of Alzheimer's patients [2].

The most significant challenge is becoming older; over the past two hundred years, researchers have focused on discovering treatments for conditions that are directly linked to aging and have only arisen because of it. If we could turn back the hands of time, we wouldn't have to worry about Alzheimer's disease or any of the other ailments that come with being older.

Figure 1. Cross-Species Comparison of PCD in Aging [3].

References:

Bulterijs, S., et al., It is time to classify biological aging as a disease. Front Genet, 2015. 6: p. 205.
Swerdlow, R.H., Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging? Neurobiology of Aging, 2007. 28(10): p. 1465-1480.
Tower, J., Programmed cell death in aging. Ageing Res Rev, 2015. 23(Pt A): p. 90-100.

(3) 00:10:23 What Causes Aging? The Epigenome

The subject is contentious since aging researchers propose many fresh concepts to get fame. Yet there are eight to nine primary causes of aging, called hallmarks because their causes were powerful. The nice thing about these aging reasons is that most scientists agree and discuss them together. Every scientist contributed. Scientists sometimes disagreed. They even wrecked each other's careers since they didn't like fresh scientists.

Longevity Genes: In the year 1990, scientists believed that free radicals did not play a role in the aging process. Instead, they believed that the genes responsible for longevity had a role in this process. In recognition of this research, a noble prize was presented [4].

Hallmarks of Aging: Once more in the year 2000, researchers came to an agreement on how to identify novel causes of aging, commonly referred to as hallmarks of aging; the identification of these hallmarks was a significant step forward in the study of aging [5].

Epigenome: The information that is contained within the cells of a living creature is referred to as the Epigenome [6].

Figure 2. Epigenetics is Associated with Aging [7].

References

4. Bin-Jumah, M.N., et al., Genes and Longevity of Lifespan. Int J Mol Sci, 2022. 23(3).

5. López-Otín, C., et al., Hallmarks of aging: An expanding universe. Cell, 2023. 186(2): p. 243-278.

6. Bernstein, B.E., A. Meissner, and E.S. Lander, The Mammalian Epigenome. Cell, 2007. 128(4): p. 669-681.

7. Siametis, A., G. Niotis, and G.A. Garinis, DNA Damage and the Aging Epigenome. Journal of Investigative Dermatology, 2021. 141(4, Supplement): p. 961-967.

(4) 00:15:53 Cosmetic Aging

As we get older, our bodies go through a number of changes, some of which include greying hair, wrinkled skin, sagging skin on the face and neck, and a spine that curves into the shape of a C. As we get older, our bodies go through a number of changes, some of which include greying hair, wrinkled skin, and sagging skin on the face and neck. There are certain families who have people who have lived to be more than a hundred years old, but they still have the appearance of someone considerably younger than their real age. A person who is 70 years old, for instance, may have the appearance of someone who is just 50 years old. Yet, compared to other individuals, the aging process of certain people who reside in Australia or who grew up there happens more swiftly than the aging process of other people.

While many people who have grey hair survive for a longer period of time, there is no correlation between having grey hair and an increased chance of passing away. On the other hand, certain characteristics of a person's appearance, such as the depth of their wrinkles and the thickness of their skin, might provide clues about their age.

Current research in artificial intelligence has altered the course of the future of science; as a result, an AI-based system can now determine a person's age by looking at his face [8].

References:

8. Harman, D.J.A.o.t.N.Y.A.o.S., Aging: overview. 2001. 928(1): p. 1-21.

(5) 00:17:15 Development Never Stops, Horvath Clock

The ages of 12 or 15, or even 25, do not mark the end of a person's developmental trajectory. The progression of an organism's development follows what's known as a "developmental arc," which is a pattern that lasts for the length of the life of the organism.

There are some portions of the developmental arc:

Infancy
Puberty

These early phases of childhood and puberty, which are both fast stages of aging, mean that growth hormones are at their height, with puberty especially being the moment in life when growth hormones reach their highest levels.

Is Aging faster during infancy and puberty?

Dr. David Sinclair says Horvath's clock, sometimes known as a biological clock, and an organism's chronological age are completely different. As said, a new AI-based approach can properly predict biological age. Internal age refers to an individual's internal organs. AI can analyze facial skin and determine organ ages. Horvath's clock states that children and adolescents age rapidly. As life continues, the graph becomes linear [9].

2. Is Developmental genes cause aging?

Those early developmental genes are the ones that don't get turned on, which ultimately leads to aging e.g. DUX4, GATA3, OCT4, HPAT5, XIST, XACT, PODXL, SOX17 [10]. These genes induce a disruption in the system later in life, which accelerates the aging process.

3. What causes scratches in DNA?

Professor Dr. David mentioned damaged chromosomes, DNA damage, and DNA breaks as major contributors. Any radiation can harm DNA. X-rays, cosmic rays, and sun exposure can cause this. Broken chromosomes from any radiation increase the unraveling of magnificent DNA loops. At the laboratory of Professor Dr. David Sinclair, an experiment was carried out using a mouse. Sinclair aged the mouse 50% faster. This mouse had kyphosis, a bent spine, grey hair, and aged organs, proving that aging can be regulated [11].

The process of becoming older can be sped up when there is a large degree of cell damage or stress. The depletion of adenosine triphosphate (ATP) is the root cause of the extensive damage done to the cells. Increased permeability of the cell membrane, The disruption of metabolic processes, particularly those involved in the production of protein [12].

References:

9. Griffiths, P.E.J.P.o.S., Genetic information: A metaphor in search of a theory. 2001. 68(3): p. 394-412.

10. Fraga, M.F. and M.J.T.i.g. Esteller, Epigenetics and aging: the targets and the marks. 2007. 23(8): p. 413-418.

11. Hobert, O., I. Carrera, and N. Stefanakis, The molecular and gene regulatory signature of a neuron. Trends Neurosci, 2010. 33(10): p. 435-45.

12. Edqvist, P.H., et al., Expression of human skin-specific genes defined by transcriptomics and antibody-based profiling. J Histochem Cytochem, 2015. 63(2): p. 129-41.

(6) 00:20:12 Puberty Rate as a Determinant of Aging Rate

Puberty speeds up aging. Studies show that the slower your puberty pace, the healthier your life and the longer you will live. Growth hormones accelerate aging. It can smooth skin and change a person's body. It might also bring temporary delight due to heavy muscles. Like burning both ends of a candle, growth hormones have many negative effects. Lower hormone levels help people live longer [13,14]. Professor Dr. David Sinclair's lab researcher Michael Bankowski tested mice. In the lab, mutant mice are dwarfed yet live longer than wild-type mice. His mutant mice lived twice as long as wild mice and had a lifetime of roughly five years, compared to the usual mouse lifespan of two years. Fasting, calorie restriction, and growth hormone deficiency were tested in mice [15].

Some people live for a longer period of time than others, such as those who dwell in South America and have a dwarf mutation; these people are also referred to as Lauren dwarfs. They also exhibited distinctive characteristics, such as increased resistance to a variety of age-related disorders, such as Alzheimer's and Parkinson's. Because of their one-of-a-kind genetic makeup, even cancer and heart illnesses do not affect them [16].

Figure 3. Delayed Puberty Causes Longevity [17].

References:

13. Forbes, G.B., Human body composition: growth, aging, nutrition, and activity. 2012: Springer Science & Business Media.

14. Duffy, G., et al., Confounders mediate AI prediction of demographics in medical imaging. npj Digital Medicine, 2022. 5(1): p. 188.

15. Horvath, S. and K.J.N.R.G. Raj, DNA methylation-based biomarkers and the epigenetic clock theory of ageing. 2018. 19(6): p. 371-384.

16. Ortega, N.M., et al., Functional genetics of early human development. Current Opinion in Genetics & Development, 2018. 52: p. 1-6.

17. Polo, S.E., S.P.J.G. Jackson, and development, Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. 2011. 25(5): p. 409-433.

(7) 00:23:00 Fasting, Hunger & Food Choices:

There is a correlation between the size of your body and the amount of time you spend in this world. If you have a large physique, your life expectancy will be lower. Nonetheless, this does not imply that your early Epigenome or your genome has complete control over your life. If a person adopts a lifestyle that is more beneficial to their health, they have the opportunity to change and modify their Epigenome if they so choose. The fact that epigenetics are responsible for controlling 80% of the characteristics of your body is a significant finding.

Is fasting good for our bodies?

The idea that "no one should be hungry" is prevalent in many parts of the world. They would go out and get snacks to consume in between meals. As a consequence of this, many people do not know what it is like to be hungry since they eat more frequently than the recommended three times a day, which is unhealthy. According to the findings of research on longevity conducted by Dr. David Sinclair, the only animals that survive beyond 30% and remain healthy are those that do not consume food. This behavior was seen in dogs, monkeys, and mice. This was discovered in 1930 by a team of scientists led by Claude Mckay. Using the use of cellulose, Mckay was able to reduce the number of calories used by the rats, which resulted in the animals living 30% longer. In the year 2000, Professor Dr. David Sinclair and his colleagues discovered genes associated with the human lifespan. These genes protect against cancer as well as other degenerative disorders. Seven genes include "sirtuins."

There was the discovery in 2005, which shows that if someone had a low insulin level and some other molecule called insulin-like growth factor, these low-level hormones turn on longevity genes, the important longevity genes are SIRT1, CLEC-196, HIL-7, TTH-1, and F20C5 [18]. High insulin levels "off" these genes. Feeding oneself accelerates life.

A few years ago, the National Institutes of Health (NIH) published a study in which he fed different combinations of fats, proteins, and carbohydrates to 10,000 mice. He had two groups of mice. One group was fed all the time, and the other group was only fed for an hour a day. He found that both groups had the same number of calories because the mice in both groups ate a lot in that hour. In this test, the group that was fed for an hour lived longer. What mice eat doesn't matter as much as when they eat [19].

When to eat, and when to avoid food?

Skipping one meal a day is a healthy option. To avoid hunger, Professor Dr. David Sinclair skips breakfast and consumes more liquids. If someone wants to adopt this habit, he/she will feel hungry in the first two to three weeks and want to eat something, but try to make this habit through the first three weeks and do without breakfast or dinner, you will adopt this habit after a few weeks, some people are very hungry in the morning so they had to skip dinner, this habit can keep someone healthier. Our liver regulates blood glucose by adding glucose. Avoid lunch and eat vegetables, fish, shrimp, and steak for supper [20].

If one stomach can't digest steak, another can. Everyone must know their stomach's optimal diet and food. Professor Dr. David quit consuming sweets and desserts at 40. Professor claimed he didn't have plaque anymore since he changed his diet. Bacteria in the mouth die without sugar.

References:

18. Townes, F.W., K. Carr, and J.W. Miller, Identifying longevity associated genes by integrating gene expression and curated annotations. PLoS Comput Biol, 2020. 16(11): p. e1008429.

19. Mitchell, S.J., et al., Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories. Cell Metab, 2019. 29(1): p. 221-228.e3.

20. De Cabo, R., et al., The search for antiaging interventions: from elixirs to fasting regimens. Cell, 2014. 157(7): p. 1515-26.

(8) 00:32:44 Fasting Schedules, Long Fasts, (Macro)Autophagy

Once a month, going without food for two days, also known as fasting, can have tremendous benefits in terms of increasing your lifespan. This is because fasting activates the autophagy system, which is responsible for digesting old and misfolded proteins as well as toxic conformations. A number of neurodegenerative diseases are characterized by the accumulation and clumping together of misfolded proteins [21]. When we get upset, a process in our body called "Macro autophagy" begins to clear out our cells in a way that is quite normal [22].

Chaperone-mediated autophagy was discovered by Ana Maria Cuervo, a researcher at Albert Einstein College of Medicine. This mechanism is responsible for the body's natural cleansing processes. Proteins that have folded incorrectly are eliminated from our bodies by this mechanism. The most remarkable finding from this study is that older mice, in which this system is on, live 35% longer than older mice in which the system is not activated. This finding is the result of turning on this system in older mice [23].

Figure 4. Chaperone-mediated autophagy [24].

References:

21. Lin, F. and Z.H. Qin, Degradation of misfolded proteins by autophagy: is it a strategy for Huntington's disease treatment? J Huntingtons Dis, 2013. 2(2): p. 149-57.

22. Cheng, C. and Z.-G. Liu, Autophagy and the Metabolism of Misfolding Protein, in Autophagy: Biology and Diseases: Basic Science, Z.-H. Qin, Editor. 2019, Springer Singapore: Singapore. p. 375-420.

23. Cuervo, A.M. and E. Wong, Chaperone-mediated autophagy: roles in disease and aging. Cell Research, 2014. 24(1): p. 92-104.

24. Bejarano, E. and A.M.J.P.o.t.A.T.S. Cuervo, Chaperone-mediated autophagy. 2010. 7(1): p. 29-39.

(9) 00:34:50 Caffeine, Electrolytes

As caffeine directly binds to SIRT3 and causes it to increase its affinity for binding substrates, hence activating sirtuin pathways, consuming caffeine during periods of fasting is beneficial [31].

While you are fasting, drinking electrolyte water can help you stay hydrated while also ensuring that you do not fall behind on your electrolyte consumption. Not only does drinking electrolyte water assist maintain fluid equilibrium in the body, but it also helps restore the minerals that might be depleted via activities such as exercise and intermittent fasting.

References:

25. Xu, H., et al., Caffeine Targets SIRT3 to Enhance SOD2 Activity in Mitochondria. Front Cell Dev Biol, 2020. 8: p. 822.

(10) 00:35:56 Blood Glucose & the Sirtuins; mTOR

Longevity genes are connected with each other’s, sugar and insulin levels in the bloodstream triggering sirtuins [26]. The mTOR system is another part of the body that works by keeping track of how much protein and amino acid we take in. Sirtuins are turned on when you fast, which is good for your health. You won't get enough of three important amino acids when you're fasting: leucine, lysine, and valine. When this happens, your body makes more Sirtuins and less mTOR. This going up and down is very important for the health of your body. Fasting also turns on your body's defense system by breaking down old proteins, making insulin more sensitive, repairing cells, and giving you energy [27]. These two pathways play an essential part in determining how long people live.

References:

26. Satoh, A., L. Stein, and S. Imai, The role of mammalian sirtuins in the regulation of metabolism, aging, and longevity. Handb Exp Pharmacol, 2011. 206: p. 125-62.

27. Saxton, R.A. and D.M. Sabatini, mTOR Signaling in Growth, Metabolism, and Disease. Cell, 2017. 168(6): p. 960-976.

(11) 00:37:55 Amino Acids: Leucine, “Pulsing”

It would appear that stimulating the mTOR signaling pathway is the primary mechanism via which leucine and other necessary amino acids drive human muscle protein synthesis [28].

Is leucine a pro-aging amino acid?

The answer is yes; Leucine immediately promotes skeletal muscle anabolism and has the ability to overcome the anabolic resistance that comes with aging. There is evidence to imply that leucine is a pro-ager [29].

Should you supplement with growth hormones or testosterone?

If someone wants to use these supplements, he should have to perform enough exercise at the proper time, to avoid any adverse health conditions. The answer is that these supplements provide you with rapid advantages of strengthening muscles. Based on research studies indicate that it influences health.

Who is Ori Hofmekler, and his story?

Israeli special forces employed Ori Hofmekler. His best-known book, "The Warrior Diet," hasn't received much notice since its release. He's over 70. In this book, he states he ate maybe once every three days in the Israeli special forces. He's fit. He's powerful and lean. Ori started the warrior diet—intermittent fasting. He liked fasting because of its incredible benefits. Pulsing stress-reacts cells. Modern individuals sit a lot and those who don't exercise age rapidly. Exercising and eating less slows aging more than not doing so.

Dr. David Sinclair Research:

He discovered that giving mice an injection of resveratrol, which is a chemical that can be found in red wine, made the mice more resistant to the negative effects of a diet heavy in fat and provided the animals with organs that were slimmer. They also had a somewhat longer lifespan, but not by a significant amount. They have a shorter lifespan as a result of being fed a diet that is heavy in fat and low in resveratrol. These mice are protected from the harmful consequences of consuming a diet high in fat thanks to resveratrol. In addition, the mice who were administered resveratrol on the second day and were allowed to eat a regular meal had a much longer lifespan than any of the other groups. Although it is often believed that resveratrol does not extend the lifespan of humans, research has shown that it does so in mice [30].

References:

28. Drummond, M.J. and B.B. Rasmussen, Leucine-enriched nutrients and the regulation of mammalian target of rapamycin signalling and human skeletal muscle protein synthesis. Curr Opin Clin Nutr Metab Care, 2008. 11(3): p. 222-6.

29. Borack, M.S. and E. Volpi, Efficacy and Safety of Leucine Supplementation in the Elderly. J Nutr, 2016. 146(12): p. 2625s-2629s.

30. Pallauf, K., et al., Resveratrol and Lifespan in Model Organisms. Curr Med Chem, 2016. 23(41): p. 4639-4680.

(12) 00:44:35 Metformin, Berberine

Metformin is a drug that mimics low energy, it is a drug given to type 2 diabetic patients, and it acts by dropping blood glucose levels down. It is found that patients having type 2 diabetes live longer because of Metformin, actually, this drug is a longevity drug. It also protects patients from cancer, heart disease, and dementia.

Type 2 diabetics take metformin to lower blood glucose and boost energy. Metformin, a longevity medicine, helps type 2 diabetics live longer. It prevents cancer, heart disease, and dementia. Metformin with resveratrol improves health. Metformin inhibits ATP production, reducing stamina. Metformin-built muscle exhibited the same strength and energy and fewer inflammation and aging indicators. Metformin is not needed during exercise to gain muscle mass. Only American doctors can prescribe metformin for health and longevity. It is a fallacy that metformin prevents exercise. False. Stomach-sensitive patients should avoid metformin. Metformin is the most prescribed oral hypoglycemic for type 2 diabetes globally. Metformin slows aging in model organisms and reduces cancer and neurological diseases in people. Metformin's anti-aging mechanisms remain unknown [31].

Berberine, which comes from the Barco tree, is an energy booster similar to AMPK and metformin. Mice on a high-fat diet became healthier when given berberine. Clinical tests have shown that it is safe to consume. Insulin sensitivity is increased with higher dosages. Prevents diabetes of the type 2 kind. When diabetes patients took berberine, their HbA1c levels decreased by a significant amount [32]. This medication greatly affected animal metabolic pathways. Berberine can also control blood glucose, cholesterol, insulin resistance, and inflammatory response in metabolic syndrome patients [33]. Berberine may shorten the lifespan of worms, according to findings that have just emerged from the Caenorhabditis laboratory. Yet, there is no need for concern because humans are not like worms, and it is perfectly safe to provide this medication to human patients and drosophila as shown in this study [34].

References:

31. Soukas, A.A., H. Hao, and L. Wu, Metformin as Anti-Aging Therapy: Is It for Everyone? Trends Endocrinol Metab, 2019. 30(10): p. 745-755.

32. Yin, J., H. Xing, and J. Ye, Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism, 2008. 57(5): p. 712-7.

33. Cao, C. and M. Su, Effects of berberine on glucose-lipid metabolism, inflammatory factors and insulin resistance in patients with metabolic syndrome. Exp Ther Med, 2019. 17(4): p. 3009-3014.

34. Navrotskaya, V.V., et al., Berberine Prolongs Life Span and Stimulates Locomotor Activity of Drosophila melanogaster. Am J Plant Sci, 2012. 3(7a): p. 1037-1040.

(13) 00:50:29 Resveratrol, Wine

Resveratrol is good for health, and red wine is a good source of resveratrol [35]. If you want to acquire enough resveratrol, all you need is one glass of red wine, but drinking more than that might lead to fatty liver disease. Pure resveratrol is either light grey or white in color. Resveratrol that has been tainted by contaminants appears brown in hue. Resveratrol or any other substance that has been tainted in any way might induce diarrhea. If someone wishes to take resveratrol internally, they should be required to mix it with yogurt, curcumin, or olive oil. You did not achieve a better result by merely adding anything to the water.

What is the specific protocol for Resveratrol?

Take some yogurt, add some resveratrol to the top of the yogurt, and swirl the mixture until the resveratrol is completely dissolved in the yogurt. Olive oil also contains fatty acids, such as monounsaturated fatty acids like oleic acid, which are known to activate sirtuin defenses and reduce the risk of chronic disease. You may also consume resveratrol by mixing a glass of resveratrol with a little bit of vinegar and then adding a couple of tablespoons' worth of olive oil to the mixture.

References:

35. Weiskirchen, S. and R. Weiskirchen, Resveratrol: How Much Wine Do You Have to Drink to Stay Healthy? Adv Nutr, 2016. 7(4): p. 706-18.

(14) 00:53:20 What Breaks a Fast?

Calorie-containing food and drink of many kinds. In the strictest sense, a fast can be broken by the consumption of any number of calories. If a person is following a stringent fasting schedule, they need to abstain from consuming any food or drink that has calories in it. Individuals who are adhering to a modified fasting diet are often allowed to consume up to twenty-five percent of the calories that they require on a daily basis while they are fasting.

(15) 00:56:45 Resveratrol, NAD, NMN, NR; Dosage, Timing

Two genes were discovered by Dr. David Sinclair, one of which was identified in yeast and the other in mammals. Haim Cohen, one of his post-doctoral students, is also the author of research on sirtuin genes. Mice can have an extended lifespan if their sirtuin genes are activated. This is a perfectly natural manner for sirtuins to display their job for the world to see. The production of proteins from genes takes place via a process known as translation. Those who want these genes to function properly should engage in physical activity and observe a fasting regimen. Resveratrol, NAD, NMN, and NR are some of the supplements that may be used in order to activate sirtuins.

Resveratrol protects and activates sirtuins. Scientists gave all organisms resveratrol to check vitality, also, Resveratrol reduces lipogenesis and inflammation in mice, preventing hepatic steatosis. In mice fed a high-fat diet, resveratrol stimulates mitochondrial biogenesis and reduces oxidative stress in regulatory T cells [36].

NAD+ controls Sirtuin metabolism and circadian rhythm. Aging reduces NAD+, changing sirtuin. Depletion and NAD+ biosynthesis deficit may lower NAD+. NAD activates sirtuins in chemical and metabolic processes. All metabolic functions require NAD. Aging reduces NAD. NAD controls human sirtuins. Resveratrol and NAD are essential for Longevity [37]. In a few days, NMN can make twice as much NAD as it did before. There are a lot of other things you can do to get more NAD in your blood. NR can be in the food you eat. We need Laxter Phosphate, which is another name for NR. Vitamin B3 is used to make NR, and it can also be found in dairy products. When NMN was given to old mice, they ran 50% faster than mice that didn't get it. Because NMN can give mice more energy and make their blood flow faster.

Which NMN Should We Buy?

NMN can be injected, capsuled, sublingually, or powdered. NMN supplements are best taken sublingually as capsules or tablets. Liposomal NMN protects the supplement from stomach acid and ensures its efficacy.

Figure 5. Sirtuins Metabolism [38].

References:

36. Bhullar, K.S. and B.P. Hubbard, Lifespan and healthspan extension by resveratrol. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2015. 1852(6): p. 1209-1218.

37. Imai, S. and L. Guarente, NAD+ and sirtuins in aging and disease. Trends Cell Biol, 2014. 24(8): p. 464-71.

38. Chang, H.C. and L. Guarente, SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab, 2014. 25(3): p. 138-45.

(16) 01:09:10 Are Artificial Sweeteners Bad for Us?

Although artificial sweeteners may have had a negligible impact on the general health of our bodies, there is no evidence that they shorten people's lifespans. Even in the case of diet coke, there is no evidence to suggest that drinking it has a negative impact on one's health. The use of sugary soda and meals high in sugar had negative effects on health, however, drinking diet coke did not have a significant negative influence on a person's body. Because it is made from natural materials, sucralose is a superior alternative to soft drinks. The media is attempting to propagate erroneous information about them, but before passing judgment, a scientist ought to investigate both of them and the components that make them up. Studies have conclusively demonstrated that artificial sweeteners are linked to a variety of adverse health effects, including weight gain, brain tumors, bladder cancer, and many more. In human studies, there has been evidence of a variety of health-related adverse consequences, including carcinogenicity [39].

References:

39. Tandel, K.R., Sugar substitutes: Health controversy over perceived benefits. J Pharmacol Pharmacother, 2011. 2(4): p. 236-43.

(17) 01:12:04 Iron Load & Aging

Senescent cells are activated when an individual takes in an excessive amount of iron, according to the findings of a recent study that was carried out in Spain by the lab of Manuel Serrano. Due to the fact that they accumulate as a person becomes older, these cells are also referred to as "zombie cells." They result in inflammation and have been linked to an increased risk of cancer. You will be able to extend your lifespan and maintain good health for the rest of your life if you reduce the quantity of these cells in your body. How can we decrease the number of these cells? Keeping a lid on your iron consumption is an easy way to do this. Iron has been shown to hasten the aging process in the body [40].

References:

40. Scudellari, M.J.N., To stay young, kill zombies. 2017. 550(7677): p. 448-450.

(18) 01:15:05 Blood Work Analysis

InsideTracker utilizes, what it believes to be the five most important indicators of health (testosterone, glucose, vitamin D, hs-CRP, and ALT). The latter two are a protein that raises your chance of heart disease and an enzyme that raises your risk of liver damage. Both of these are harmful.

(19) 01:19:37 C-Reactive Protein, Cholesterol: Serum & Dietary
CRP Proteins:

A sensitive marker for cardiovascular inflammation, CRP clears bacteria, dying, and mutated cells, and may have more complicated immunomodulatory effects [41]. This protein also predicts longevity. Patients with high levels of CRP should have to drop down its level, as someone gets old CRP level raises. How to get down CRP level? Changing your diet, eating vegetables, and drugs will also help you, but natural treatment would be a good option. A patient who already has an increased level of CRP and has a high CRP level may suffer a heart attack.

Cholesterol:

There are two major categories of cholesterol, Low-Density Lipoprotein LDL and High-Density Lipoprotein HDL. Statins medicines are a group of medicines that can help lower LDL levels, some people say that it might cause Alzheimer but it’s not true. PCSK9 inhibitor also inhibits LDL, Its acts by blocking the release of LDL from the liver, thus cholesterol level drop-down in the bloodstream [42]. Sometimes an individual eats nothing but will have high cholesterol levels, it is due to Familial hypercholesterolemia [43]. Dietary cholesterol causes no impact on bloodstream cholesterol.

References:

41. Rhodes, B., B.G. Fürnrohr, and T.J. Vyse, C-reactive protein in rheumatology: biology and genetics. Nature Reviews Rheumatology, 2011. 7(5): p. 282-289.

42. Levine., B.P.W.C.Y.S.N., StatPearls.

43. Defesche, J.C., et al., Familial hypercholesterolaemia. Nature Reviews Disease Primers, 2017. 3(1): p. 17093.

(20) 01:26:02 Amino Acids, Plants, Antioxidants

Dietary restriction (DR) and nutritional signaling pathways have been related to lifespan and health span in model species. Serine, threonine, and valine in media activate independent but related pathways to sensitize and age yeast cells. Protein or necessary AA limitation enhances rodent longevity and health span [44]. Eating Plants gives us a lot of benefits, it’s also a good source of vitamins and it also had high nutritional value. Spinach is also a good source of vitamins. When the plant gets stressed they release certain molecules e.g. Resveratrol is one of the major molecule the plant releases during stress. Quercetin also activates the Sirtuins.

Antioxidants will not affect someone's health unless used in higher doses. Our body's immune system needs antioxidants. Antioxidants didn’t overcome the side effects of aging, or they didn’t play any role in longevity. Before the entry of Resveratrol in longevity research it was thought that this substance is good for human health because Resveratrol is an antioxidant.

References:

44. Mirzaei, H., J.A. Suarez, and V.D. Longo, Protein and amino acid restriction, aging and disease: from yeast to humans. Trends Endocrinol Metab, 2014. 25(11): p. 558-66.

(21) 01:33:45 Behaviors That Extend Lifespan, Testosterone, Estrogen

There is evidence that Exercise can enhance Sirtuins in the body, and thus improves longevity by activating longevity genes. Exercise improves oxidative metabolism efficiency, biogenesis, and sirtuin activity/expression [45]. A study shows that Testosterone levels decline with age [46]. By switching to a natural diet, however, one is able to keep their testosterone levels at a healthy and normal level.

According to one study, the levels of estrogen in mice dropped when they were put on a fast with low caloric intake for some period of time, but they rose again when they were given a healthy diet.

References:

45. Vargas-Ortiz, K., V. Pérez-Vázquez, and M.H. Macías-Cervantes, Exercise and Sirtuins: A Way to Mitochondrial Health in Skeletal Muscle. Int J Mol Sci, 2019. 20(11).

46. Stanworth, R.D. and T.H. Jones, Testosterone for the aging male; current evidence and recommended practice. Clin Interv Aging, 2008. 3(1): p. 25-44.

(22) 01:40:35 Neuroplasticity & Neural Repair

The nervous system's capacity to reshape its structure, functions, and connections in response to intrinsic or external stimuli following injuries. Sirtuins stop neurodegeneration. They diminish harmful protein aggregates, boost brain plasticity by upregulating learning and memory genes, improve mitochondria function by decreasing oxidative stress, and reduce persistent chronic inflammation by inhibiting NF-B and epigenetic processes [47]. The memory cell is also controlled by Sirtuins. It also improves synaptic plasticity, epigenetic control, and oxidative stress-related mitochondrial function, which may enhance cognition [48].

Also Through DNA methylation, mammalian tissues may access young epigenetic information to boost tissue function and regeneration in vivo [55]. The laboratory of Dr. David Sinclair will begin conducting clinical tests of a gene transfer procedure on monkeys, and eventually on people, in the hope of curing sufferers with ocular blindness. This gene transfer can be accomplished through a variety of methods; however, injection or the use of a pill will be an effective vector for gene transformation.

References:

47. Min, S.W., et al., Sirtuins in neurodegenerative diseases: an update on potential mechanisms. Front Aging Neurosci, 2013. 5: p. 53.

48. Fagerli, E., et al., Sirtuins and cognition: implications for learning and memory in neurological disorders. Front Physiol, 2022. 13: p. 908689.

(23) 01:46:19 Ice Baths, Cold Showers, “Metabolic Winter”

Athletes have long relied on ice baths as a post-workout recovery method to soothe aching muscles and reduce inflammation after strenuous activity. Ice baths lower muscle pain and soreness. A cold bath provides your body with a "cold water shock," which can stimulate the immune system by increasing the synthesis of white blood cells and antioxidants in the body. When someone gets chilly, their body burns energy via metabolic activity to warm their organs. This is referred to as metabolic winter [49].

References:

49. Lu, Y., et al., Reprogramming to recover youthful epigenetic information and restore vision. Nature, 2020. 588(7836): p. 124-129.

(24) 01:48:07 Obesity & How It Accelerates Aging, GnRH

NAD levels decline with age and nutritional disturbances like obesity, according to several research. Diabetes and fatty liver disease are also linked to NAD deficiency [50]. Obesity shortens people's lifespans and has effects on cellular and molecular processes that are analogous to those of aging, respectively [51]. The number of senescent cells in the adipose tissue likewise rises with obesity. Senescent cells in fatty tissue are responsible for inducing inflammatory reactions, which in turn causes the organism to age more quickly.

Hypothalamic genes SIRT1 and SIRT2 increase lifespan. In mice, suppressing hypothalamic inflammation increases GnRH, a longevity gene [52]. The life span of animals can be increased by reducing the amount of inflammation that occurs in the hypothalamus.

Figure 6. In chow-fed control male mice, the thymus appeared "fatty" in age-matched 13-month-old animals, associated with increased body weight and a reduction in the total number of thymic cells [53].

References:

50. Cronise, R.J., D.A. Sinclair, and A.A. Bremer, The "metabolic winter" hypothesis: a cause of the current epidemics of obesity and cardiometabolic disease. Metab Syndr Relat Disord, 2014. 12(7): p. 355-61.

51. Okabe, K., et al., Implications of altered NAD metabolism in metabolic disorders. J Biomed Sci, 2019. 26(1): p. 34.

52. Salvestrini, V., C. Sell, and A. Lorenzini, Obesity May Accelerate the Aging Process. Front Endocrinol (Lausanne), 2019. 10: p. 266.

53. Wang, Z., et al., GnRH pulse frequency and irregularity play a role in male aging. Nature Aging, 2021. 1(10): p. 904-918.

(25) 01:52:10 Methylation, Methylene Blue, Cigarettes

DNA methylation involves DNA methyl transferases covalently attaching a methyl group to the C-5 position of the cytosine ring of DNA [54]. Smoking and a lack of physical activity both cause an excess of methylation in the DNA; as a consequence, this switches off numerous genes, which ultimately leads to a serious sickness.

Figure 7. The information contained in DNA methylation clocks is both chronological and biological in nature [55].

References:

54. Jin, B., Y. Li, and K.D. Robertson, DNA methylation: superior or subordinate in the epigenetic hierarchy? Genes Cancer, 2011. 2(6): p. 607-17.

55. Bell, C.G., et al., DNA methylation aging clocks: challenges and recommendations. Genome Biology, 2019. 20(1): p. 249.

(26) 01:56:17 X-Rays

Many studies have revealed a correlation between exposure to dental X-rays and an increased risk of developing brain cancer [56]. There have been a few instances in which an x-ray that was performed by a doctor as part of a medical evaluation did not kill someone. Yet if a greater amount of radiation was employed, the outcome would be negative.

Figure 8. X-ray Side effects On Health [57].

References:

56. Hwang, S.Y., et al., Health effects from exposure to dental diagnostic X-ray. Environ Health Toxicol, 2018. 33(4): p. e2018017.

57. Lu, L., et al., High energy X-ray radiation sensitive scintillating materials for medical imaging, cancer diagnosis and therapy. Nano Energy, 2021. 79: p. 105437.

(27) 01:59:00 Public Science Education, Personal Health

In today's world, a great deal of the information that can be found on social media is inaccurate; even while some of this material originates from knowledgeable sources, it still ends up leading others astray. The general public will not be able to comprehend the study work that has been published by scientists unless these specialists begin producing live podcasts in which they invite specialized field experts.

(28) 02:05:40 The Sinclair Test You Can Take: www.doctorsinclair.com

According to Dr. David Sinclair, the laboratory in which he works is now offering a test with which an individual may not only forecast his future health and mortality but also take action to alter his Epigenome. Visit the website doctorsinclair.com; by gaining access to this site, a person may learn more about his current and future health, among other things. A person who is 90 years old will be able to turn back the clock on his or her biological age and return it to anywhere between 30 and 40 years in the future as a result of recent developments in human longevity [58].

References:

58. Karunadharma, P.P., et al., Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects. Aging Cell, 2015. 14(4): p. 547-57.

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Huberman Lab Podcast - “Slowing & Reversing Aging"