David Sinclair of Harvard- Review of Lifespan: Why We Age—and Why We Don't Have To

Who is Dr. David Sinclair? And what is his Research about?

David Sinclair is a renowned Harvard professor, biologist, and researcher who has spent decades studying the aging process and how to extend human lifespan. His groundbreaking book, "Lifespan: Why We Age—and Why We Don't Have To," explores the latest scientific research on aging and presents a bold new vision for how we can potentially slow, stop, and even reverse the aging process.

Sinclair's ideas are important because aging is the greatest risk factor for many of the diseases that afflict us as we get older, including cancer, Alzheimer's disease, and heart disease. If we can find ways to slow or reverse the aging process, we could potentially extend healthy human lifespan and improve quality of life for millions of people around the world.

Sinclair's research has focused on the role of molecules like nicotinamide adenine dinucleotide (NAD+) in the aging process, as well as the potential benefits of supplements, caloric restriction, intermittent fasting, exercise, and good sleep habits. His work has been widely recognized and has earned him numerous accolades, including being named one of Time Magazine's "100 Most Influential People" in 2018.

In this blog post, we will explore some of the key ideas from Sinclair's book and how they might help us extend human life.

Aging is a disease: Sinclair believes that aging is not just a natural part of life, but a disease that can be treated and possibly even cured. He argues that if we can understand the mechanisms that cause aging, we can develop treatments to slow or reverse the process.

 

Understanding Aging: What is aging and how does it work?

Aging is a complex biological process that involves a gradual decline in the function of our cells, tissues, and organs over time. While the exact mechanisms of aging are still not fully understood, scientists have identified several key factors that contribute to the aging process.

One of the main factors is DNA damage. Over time, our DNA accumulates damage from various sources, such as exposure to radiation or toxins, and this damage can cause mutations that can lead to cancer and other diseases. Additionally, the ends of our chromosomes, called telomeres, shorten each time our cells divide, and when they become too short, the cell stops dividing and eventually dies.

Another key factor in aging is the accumulation of senescent cells. These are cells that have stopped dividing but are still metabolically active and can produce harmful compounds that damage nearby cells and contribute to inflammation.

As we age, these and other factors cause our cells to become less efficient and more prone to damage and dysfunction. This can lead to a decline in the function of our tissues and organs, making us more susceptible to age-related diseases like cancer, Alzheimer's, and heart disease.

For example, as our arteries age, they become less flexible and more prone to damage, which can lead to high blood pressure and heart disease. In the brain, the accumulation of beta-amyloid protein and tau protein can disrupt neural function and lead to Alzheimer's disease. And in our cells, mutations and DNA damage can cause them to grow uncontrollably and form cancerous tumors.

Overall, aging is considered the greatest risk factor for many diseases precisely because it increases our susceptibility to damage and dysfunction in our cells, tissues, and organs, making us more vulnerable to a wide range of age-related illnesses.

Goodbye Genetics, Welcome Epigenetics!

Genetics have been the subject of much blame for many 'genetic' diseases. It seems to be an easy way out where many surrender control & blame their poor health on their parents.

Epigenetics is the study of changes in gene expression that do not involve alterations to the underlying DNA sequence. These changes can be influenced by environmental factors, such as diet or stress, and can be passed down from one generation to the next.

David Sinclair has written extensively about the role of epigenetics in health and longevity. He has suggested that epigenetic changes, which can accumulate over time, may play a significant role in aging and age-related diseases. Sinclair believes that while genetics plays a role in how long we live, it is not the only determining factor. In fact, he believes that our environment and lifestyle choices have a much bigger impact on our longevity than genetics.

Sinclair's research has focused on the genetic and molecular mechanisms that contribute to aging and age-related diseases. He has discovered several genes and pathways that can influence how long we live, such as the SIRT1 gene, which is involved in regulating cellular metabolism and can extend lifespan in experimental organisms.

Sinclair points to the fact that people in certain regions of the world, such as Okinawa, Japan, and the Nicoya Peninsula in Costa Rica, tend to live longer than people in other parts of the world. This is likely due to a combination of genetic and environmental factors, such as a healthy diet, active lifestyle, and strong social support networks.

Similarly, Sinclair believes that lifestyle choices, such as avoiding smoking and excessive alcohol consumption, can have a significant impact on lifespan. He has also conducted research on the benefits of intermittent fasting and calorie restriction, which can mimic the effects of a healthy diet and exercise on longevity.

The Hallmarks of Aging: Understanding the Aging Process

The nine hallmarks of aging were first proposed in a 2013 paper by scientists from the Buck Institute for Research on Aging and other institutions. These hallmarks are:

1. Genomic instability: This hallmark refers to the accumulation of DNA damage and mutations over time, which can lead to cellular dysfunction and disease. According to Sinclair, one way to address genomic instability is to boost the activity of enzymes called sirtuins, which can repair damaged DNA and protect cells from oxidative stress (Sinclair, 2019).
2. Telomere attrition: Telomeres are the protective caps on the ends of our chromosomes, and they shorten with each cell division. When telomeres become too short, cells stop dividing and eventually die. Sinclair has suggested that boosting the activity of the enzyme telomerase, which can lengthen telomeres, could help to slow or reverse the aging process (Sinclair, 2019).
3. Epigenetic alterations: Epigenetic changes are modifications to our DNA that can affect gene expression and cellular function. These changes can accumulate over time and contribute to aging and disease. Sinclair has suggested that interventions like caloric restriction and supplements like resveratrol and metformin can help to reverse some epigenetic changes and improve cellular function (Sinclair, 2019).
4. Loss of proteostasis: Proteostasis refers to the ability of our cells to maintain the proper balance of proteins and prevent the buildup of damaged or misfolded proteins. As we age, this system becomes less efficient, which can contribute to the development of diseases like Alzheimer's and Parkinson's. Sinclair has suggested that boosting the activity of the chaperone protein HSP90 could help to restore proteostasis and improve cellular function (Sinclair, 2019).
5. Deregulated nutrient sensing: This hallmark refers to the dysregulation of signaling pathways that detect and respond to nutrients like glucose and amino acids. Sinclair has suggested that interventions like caloric restriction and supplements like resveratrol and rapamycin can help to restore nutrient sensing and improve cellular function (Sinclair, 2019).
6. Mitochondrial dysfunction: Mitochondria are the powerhouses of our cells, and they produce energy through a process called oxidative phosphorylation. However, over time, our mitochondria can accumulate damage, leading to decreased energy production and increased production of harmful byproducts like reactive oxygen species (ROS). Mitochondrial dysfunction has been linked to numerous age-related diseases, including Alzheimer's disease and Parkinson's disease.
7. Cellular senescence: This refers to cells that have stopped dividing but remain active and can produce harmful compounds that damage nearby cells and contribute to inflammation. Cellular senescence can be triggered by various factors, including DNA damage and telomere shortening, and it has been linked to numerous age-related diseases, including cancer, Alzheimer's disease, and atherosclerosis.
8. Stem cell exhaustion: Stem cells are responsible for regenerating and repairing tissues throughout our bodies. However, over time, our stem cells can become depleted or lose their ability to differentiate into different types of cells. This can lead to a decline in tissue regeneration and repair, contributing to the aging process and increasing our susceptibility to age-related diseases.
9. Altered intercellular communication: Refers to changes in the ability of cells to communicate with each other as we age. The hallmark of altered intercellular communication encompasses various age-related changes in communication between cells, including changes in signaling pathways, altered secretion of signaling molecules, and changes in the extracellular matrix that affect the function of cell signaling.

As we age, the communication between cells becomes less efficient, leading to a decline in tissue function and the development of age-related diseases. These changes can affect many different tissues and organs in the body, including the brain, immune system, and cardiovascular system.

There are several mechanisms that contribute to altered intercellular communication during aging, including oxidative stress, inflammation, and cellular senescence. These mechanisms can lead to changes in the expression of genes and proteins involved in cell signaling, and changes in the structure and composition of the extracellular matrix.

The 9 Longevity Compounds

1- NAD+: Why David Sinclair believes that boosting NAD+ levels could be the key to extending human life

Nicotinamide adenine dinucleotide (NAD+) is a molecule found in all living cells that plays a critical role in energy metabolism and cellular homeostasis. It serves as a coenzyme, meaning that it is required for the function of certain enzymes that catalyze important biochemical reactions in the body.

As we age, the levels of NAD+ in our cells tend to decline, which can lead to a variety of negative effects on our health and well-being. For example, decreased NAD+ levels have been linked to a decline in mitochondrial function, which can contribute to age-related diseases such as Alzheimer's, Parkinson's, and cancer. NAD+ depletion has also been implicated in the development of metabolic disorders like diabetes and obesity.

2- NMN: The Supplement that Boost NAD Levels

David Sinclair has been a vocal proponent of the idea that boosting NAD+ levels could be a key strategy for extending human lifespan and improving overall health in older adults. Sinclair has conducted numerous studies showing that supplementing with compounds that increase NAD+ levels, such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), can improve mitochondrial function, reduce inflammation, and even reverse certain aspects of aging at the cellular level.

While the scientific community is still debating the potential benefits and risks of NAD+ supplementation, many experts agree that Sinclair's work has opened up exciting new avenues for research on aging and longevity.

3- Resveratrol: The Longevity Antioxidant

Resveratrol is a naturally occurring compound found in grapes, berries, and other plants. It is believed to have anti-inflammatory and antioxidant properties that may help to reduce the risk of age-related diseases. Some studies in animals have shown that resveratrol can extend lifespan and improve overall health. However, the evidence in humans is much less clear. While some studies have suggested that resveratrol may improve cardiovascular health and glucose metabolism, others have found no significant benefits. Overall, more research is needed to determine whether resveratrol is an effective supplement for promoting longevity in humans.

4- Metformin: The Diabetes Drug that Extends Life

Metformin is a drug commonly used to treat type 2 diabetes. It works by reducing glucose production in the liver and improving insulin sensitivity. Some studies have suggested that metformin may also have anti-aging effects.

Sinclair and others have proposed that metformin may have potential benefits for extending human lifespan by activating AMP-activated protein kinase (AMPK), which is involved in cellular energy regulation. Some studies have suggested that metformin may have anti-aging effects in animals, but the evidence in humans is limited. While some observational studies have suggested that people taking metformin may have a lower risk of certain age-related diseases, such as cancer and cardiovascular disease, more research is needed to determine whether metformin can truly extend human lifespan.

Metformin can have side effects, such as gastrointestinal distress and vitamin B12 deficiency, that may limit its use as an anti-aging supplement.

5- Berberine: The Poor Man's Metformin (According to Sinclair)

David Sinclair has been prescribing Metformin for his own personal use. Not all of us has access to this drug. But, thankfully, there's Berberine! 

David Sinclair has suggested that berberine, a compound found in several plants including goldenseal, barberry, and Oregon grape, may have similar effects to metformin in activating AMP-activated protein kinase (AMPK), which is involved in cellular energy regulation. In his book "Lifespan," Sinclair discusses the potential benefits of berberine as an alternative to metformin for people who want to improve their metabolic health and potentially extend their lifespan.

Berberine has been shown in some studies to have anti-inflammatory and blood sugar-lowering effects, as well as potential benefits for cholesterol levels and cardiovascular health. However, the evidence for the effectiveness of berberine in extending human lifespan is limited, and more research is needed to fully understand its potential benefits and risks.

6- Rapamycin: The mTOR Inhibitor

Rapamycin is a drug used to prevent organ rejection in transplant patients. Sinclair's research has suggested that rapamycin may have potential benefits for extending human lifespan by inhibiting a protein called mTOR, which is involved in cellular growth and metabolism. Some studies in animals have suggested that rapamycin can extend lifespan and delay the onset of age-related diseases, but more research is needed to determine whether it is safe and effective for use in humans.

7- Olive Oil: The Sirtuin Activator

David Sinclair has discussed the potential benefits of olive oil as a sirtuin activator, which could have potential implications for extending human lifespan. Sirtuins are a group of enzymes that have been linked to longevity and cellular health, and some research has suggested that certain compounds in olive oil, such as oleuropein and hydroxytyrosol, may activate sirtuins.

In his book "Lifespan," Sinclair suggests that the Mediterranean diet, which is rich in olive oil, may be one reason why people in Mediterranean countries tend to live longer and have lower rates of certain age-related diseases. In addition to potentially activating sirtuins, olive oil has been shown to have anti-inflammatory and antioxidant effects, which may contribute to its potential health benefits.

Some studies have suggested that olive oil may have potential benefits for metabolic health, cardiovascular health, and even cognitive function. However, it is important to note that not all olive oils are created equal, and some may be more beneficial than others. Extra-virgin olive oil, which is made by cold-pressing the olives without the use of chemicals, is generally considered to be the most nutritious and healthful type of olive oil.

David Sinclair has suggested that olive oil may have potential benefits as a sirtuin activator, which could have implications for extending human lifespan. The anti-inflammatory and antioxidant effects of olive oil, as well as its potential benefits for metabolic and cardiovascular health, make it a potentially healthful addition to a balanced diet.

7- Quercetin: for Reduced Inflammation & Fatigue, and Increased Cardiovascular Health

 David Sinclair has discussed the potential benefits of quercetin, a flavonoid compound found in many plant foods, for extending human lifespan and improving overall health. Quercetin has been shown to have anti-inflammatory and antioxidant effects, and some research has suggested that it may activate sirtuins, a group of enzymes that have been linked to longevity and cellular health.

In his book "Lifespan," Sinclair suggests that quercetin may have potential benefits for metabolic health, cardiovascular health, and even cognitive function. He notes that quercetin has been shown in some studies to have anti-inflammatory effects in people with conditions such as asthma and allergies, as well as potential benefits for blood pressure and cholesterol levels.

In addition to potentially activating sirtuins, quercetin has been shown to have a number of other health benefits. It may improve exercise performance and reduce fatigue, for example, and some studies have suggested that it may have potential anticancer effects. Quercetin is found in many plant foods, including onions, apples, berries, and leafy green vegetables.

8- Spermidine: Autophagy Activator

David Sinclair has discussed the potential benefits of spermidine, a naturally occurring polyamine that is found in foods such as soybeans, wheat germ, and aged cheese, for extending human lifespan and improving overall health. Spermidine has been shown to have anti-inflammatory and antioxidant effects, and some research has suggested that it may activate autophagy, a cellular process that helps to remove damaged or dysfunctional proteins and organelles.

In his book "Lifespan," Sinclair suggests that spermidine may have potential benefits for metabolic health, cardiovascular health, and even cognitive function. He notes that spermidine has been shown in some studies to have anti-inflammatory effects, as well as potential benefits for blood pressure and cholesterol levels.

In addition to potentially activating autophagy, spermidine has been shown to have a number of other health benefits. It may improve mitochondrial function, for example, which is important for cellular energy production, and some studies have suggested that it may have potential anticancer effects. Spermidine is found in a variety of foods, including soybeans, legumes, mushrooms, and some types of cheese.

9- Fisetin: Cell Health Regulator

One of the compounds that Sinclair has studied is fisetin, a naturally occurring flavonoid found in many fruits and vegetables, including strawberries, apples, and onions.

Fisetin has been shown to have a range of potential health benefits, including anti-inflammatory and antioxidant properties. However, Sinclair's interest in fisetin stems from its ability to activate sirtuins, a group of proteins that play a key role in regulating cellular health and aging.

According to Sinclair, fisetin may be able to slow down the aging process and extend lifespan by activating sirtuins, which in turn help to protect cells from damage and improve cellular function. In addition, fisetin has been shown to have other potential health benefits, including reducing the risk of age-related diseases such as cancer and Alzheimer's disease.

Caloric Restriction and Intermittent Fasting for Increased Lifespan

David Sinclair is a proponent of the idea that caloric restriction and intermittent fasting can help to extend human life. According to Sinclair, these approaches activate a family of proteins called sirtuins, which play a key role in regulating metabolism and promoting cellular health.

Caloric restriction involves reducing the number of calories consumed, typically by 30-40%, without compromising the intake of essential nutrients. Sinclair believes that this approach can stimulate the production of sirtuins, which in turn can promote DNA repair and enhance the efficiency of the mitochondria, the powerhouses of the cell. This can lead to a reduction in oxidative stress and inflammation, two factors that are associated with aging and age-related diseases.

Intermittent fasting involves alternating periods of fasting and eating, such as the 16/8 method, where one fasts for 16 hours and eats during an 8-hour window. Sinclair believes that this approach can also activate sirtuins and promote cellular health. In addition, intermittent fasting has been shown to improve insulin sensitivity, reduce inflammation, and promote weight loss, all of which are associated with improved lifespan.

Exercise and Sleep for Age-Related Disease Prevention

According to Sinclair, regular exercise and good sleep habits are two key factors that can help extend human life and prevent age-related diseases.

Regular Exercise: Sinclair believes that regular exercise can help prevent age-related diseases such as heart disease, diabetes, and dementia. Exercise is important because it helps to improve cardiovascular health, build muscle mass, and improve cognitive function. Additionally, exercise can help to reduce inflammation, which is a major contributor to many age-related diseases.

Sinclair recommends that people engage in at least 30 minutes of moderate exercise every day. This can include activities such as walking, jogging, cycling, or swimming. Additionally, he suggests that people incorporate strength training exercises into their routine to build and maintain muscle mass.

Good Sleep Habits: Sinclair also emphasizes the importance of good sleep habits in extending human life. According to him, getting adequate sleep is essential for overall health and can help prevent age-related diseases such as Alzheimer's disease, cancer, and cardiovascular disease.

Sleep is important because it allows the body to repair and regenerate, which is essential for maintaining overall health. Lack of sleep can lead to a number of health problems, including increased inflammation, cognitive impairment, and a weakened immune system.

Sinclair suggests that people aim to get at least 7-8 hours of sleep per night. Additionally, he recommends that people establish a regular sleep schedule, avoid caffeine and alcohol before bedtime, and create a comfortable sleep environment that is conducive to restful sleep. 

Conclusion:

Be well. Be safe. Be beautiful!

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References:

1. Sinclair, D. A. (2014). Epigenetic changes in aging and age-related diseases. Mechanisms of aging and development, 135, 1-3.

2. Mostoslavsky, R., Chua, K. F., Lombard, D. B., Pang, W. W., Fischer, M. R., Gellon, L., ... & Alt, F. W. (2006). Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell, 124(2), 315-329.

3. Mouchiroud, L., Houtkooper, R. H., Moullan, N., Katsyuba, E., Ryu, D., Cantó, C., ... & Schreiber, V. (2013). The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell, 154(2), 430-441.

4. Sinclair, D. A. (2011). Sirtuins for healthy aging and longevity. Science, 331(6017), 919-923.

5. Palacios, J. A., Herranz, D., De Bonis, M. L., Velasco, S., Serrano, M., & Blasco, M. A. (2010). SIRT1 contributes to telomere maintenance and augments global homologous recombination. Journal of cell biology, 191(7), 1299-1313.

6. Zhang, X., Liu, J., & Gong, Z. (2016). Epigenetic regulation of aging via sirtuins. Frontiers in physiology, 7, 186.

7. Mitchell, S. J., Bernier, M., Mattison, J. A., Aon, M. A., Kaiser, T. A., Anson, R. M., ... & Ingram, D. K. (2019). Daily fasting improves health and survival in male mice independent of diet composition and calories. Cell metabolism, 29(1), 221-228.

8. Bonkowski, M. S., Rocha, J. S., Masternak, M. M., Al Regaiey, K. A., & Bartke, A. (2006). Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proceedings of the National Academy of Sciences, 103(20), 7901-7905.

9. Sinclair, D. A. (2018). Toward a unified theory of caloric restriction and longevity regulation. Mechanisms of aging and development, 176, 34-41.

10. Frederick, D. W., Loro, E., Liu, L., Davila Jr, A., Chellappa, K., Silverman, I. M., ... & Barzilai, N. (2016). Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle. Cell metabolism, 24(2), 269-282.

 

Disclaimer - PLEASE READ: 

While Sinclair is a leading researcher in the field of longevity, the content and supplements discussed in this blog are for informational use only. Drugs and supplements can still have side effects and can interact with other medications. As with any supplement or medication, it is important to consult with a healthcare provider before starting to take berberine, especially if you have any underlying health conditions or are taking other medications.