Life Extension Magazine®
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Senolytics for Longer Life

Dr. Alan S. Green explains his therapeutic treatment against aging that includes metformin, rapamycin, fisetin, quercetin, and dasatinib.

Scientifically reviewed by: Dr. Gary Gonzalez, MD, on January 2021.

The medical establishment believes that aging is inevitable and that humans are destined to become old and sick.

Yet, Dr. Alan S. Green believes that aging can be managed and delayed through interventions such as senolytic therapies.

In his New York practice, Dr. Green uses senolytic compounds to target and remove dysfunctional senescent cells.

These compounds include a drug and two nutrients. By removing old, senescent cells, the body then produces more youthful cells that can slow aging processes and restore more youthful functionality.

In this interview with Life Extension® magazine, Dr. Green discusses the science and theory behind his innovative practice of anti-aging medicine.

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LE: You assert that there are two very different types of aging, passive and active. Can you explain your theory?

Dr. Green: Passive or natural aging is the classic concept of aging. As a result of wear and tear over time, there is slow accumulation of damage. The damaged parts include mitochondria, DNA, nuclear membranes, proteins, etc. In natural aging, the body does its best to repair the damage which accumulates.

In active aging, the organism’s own actions cause damage, decline, and death. This is the type of damage that causes age-related disease. Almost everybody dies from active aging.

LE: Is it possible to treat or slow active aging?

Dr. Green: Yes. Active aging and age-related disease are driven to a significant degree by two things: senescent cells and mTOR. They present targets for anti-aging treatments. Drugs or compounds that treat active aging must be able to prolong lifespan and prevent age-related diseases, including atherosclerotic heart disease, Alzheimer’s disease, and cancer. In mouse studies, removing senescent cells or lowering mTOR does both of these things.

LE: What exactly are senescent cells?

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Dr. Green: Senescent cells have three main characteristics:

  1. They are blocked from cell division and can’t become two new cells. This has a major impact on tissues that require stem cells to replace lost cells. For example, senescent cells contribute to age-associated cardiomyopathy (a disease of the heart muscle that makes it harder for the heart to pump blood to the body). In 70-year-old subjects, over half of cardiac stem cells are senescent and can’t form healthy new heart cells. This contributes to cardiac failure.
  2. They cause a damaging bystander effect in neighboring healthy cells, causing them to become senescent. In effect, one rotten apple spoils the barrel. In a 2018 study, injection of a small number of senescent cells in young mice spread cellular senescence into host tissues. This led to physical dysfunction and a five-fold increased risk of death.
  3. They produce what’s called a senescence-associated secretory phenotype, or SASP. This is a witch’s brew of highly active substances, including a fearsome mixture of pro-inflammatory compounds. Various SASP phenotypes cause specific diseases.

LE: What can we do about senescent cells?

Dr. Green: Senolytics are drugs or other compounds that remove senescent cells. In mouse studies, removal of senescent cells increases lifespan and ameliorates age-related disease. There is now a sufficient body of evidence to justify the introduction of senolytics into clinical anti-aging medicine.

LE: What are some effective senolytics?

Dr. Green: The main three senolytics I use are dasatinib, fisetin, and quercetin. Dasatinib is the generic name for Sprycel®, a drug approved since 1996 for the treatment of leukemia. Fisetin and quercetin are flavonoids present in fruits and vegetables. They’re sold over the counter and are known to be very safe.

My method is to use all three: 100 mg dasatinib for three days, 1,000 mg of regular quercetin for three days, 1,500 mg of regular fisetin for three days. That’s a maximum dose. Patients can begin with a smaller dose and determine sensitivity.

There are now two human studies and more than 20 animal studies regarding dasatinib’s role as a senolytic. Quercetin has been used in two human studies, and all mouse studies with dasatinib included quercetin. Fisetin had an excellent result in a 2018 mouse study. It was even more effective than quercetin, and there are several human studies using fisetin now listed on: www.clinicaltrials.gov. There have been no apparent harmful effects from long-term removal of senescent cells.

LE: What do studies of senolytics show?

Dr. Green: In mouse studies, removal of senescent cells improves cardiac function and reduces cardiovascular disease, alleviates frailty and muscle weakness, decreases osteoporosis, improves running endurance, decreases fatty liver disease and lung disease, decreases Alzheimer’s-like dementia, and in old mice, increases lifespan by 36%.

The two most recent human studies were done at the Mayo Clinic in 2019. One showed that a combination of 100 mg of dasatinib and 1,000 mg of quercetin, given orally for three days, removed senescent cells in people with diabetic kidney disease. This showed that senolytics may work similarly in humans as they do in mice.

The other study showed that 100 mg of dasatinib and 1,250 mg of quercetin, given for three consecutive days each week for three weeks, alleviated physical dysfunction and improved walking distance and speed in patients with idiopathic pulmonary fibrosis (a lung disease that makes it difficult to breathe). This demonstrated that some of the results in mice can be seen in humans.

LE: What conditions do you think can be treated with senolytics?

Dr. Green: In general, any condition or disease that gets worse with age or has increased incidence with age is likely a senescent-cell-related condition and may respond to treatment with senolytics.

This includes:

  • Aging,
  • Cancer,
  • Cardiovascular disease,
  • Alzheimer’s disease and neurodegeneration,
  • Chronic lung disease and emphysema,
  • Chronic kidney disease,
  • Non-alcoholic fatty liver disease,
  • Obesity and metabolic syndrome,
  • Osteoarthritis and osteoporosis,
  • Eye cataracts,
  • Muscle frailty,
  • And more.

LE: Besides senescent cells, you mentioned that the protein mTOR plays a role in aging. Can you explain that?

Dr. Green: Since 2009, a large body of scientific studies has shown that increased activity of mTOR (which stands for mammalian target of rapamycin, sometimes called mechanistic target of rapamycin) is a major driver of aging and age-related disease. Many of the harmful actions of mTOR actually relate to senescent cells. mTOR accelerates the production of senescent cells and increases the production of the harmful SASP that senescent cells produce.

LE: How can we reduce mTOR activity?

Scientist separating blood vials

Dr. Green: It’s been shown in some studies that the drug rapamycin can increase lifespan in animals by lowering the activity of the mTOR pathway. While senolytics kill senescent cells, rapamycin can help prevent them from developing in the first place. Rapamycin has extended the lifespan of every living thing tested in the laboratory, yeast, worms, flies, and middle-aged mice.

In a 2014 paper, it was reported rapamycin extended the median lifespan 23% in male mice and 26% in female mice.

LE: Can you talk a little about rapamycin studies that have been done on humans?

Dr. Green: In a study published in 2014, a rapalog (a rapamycin-identical compound) was used to lessen immunosenescence (the decline in immune function during aging) in elderly volunteers. It also enhanced response to influenza vaccine by about 20%. From this study we know that weekly rapamycin may be used to improve immune function in the elderly.

Another study from Taiwan involved the treatment of patients with acute respiratory distress syndrome (ARDS) due to the H1N1 strain of flu. Patients who were on respirators were given either the influenza drug Tamiflu® alone or Tamiflu® with 2 mg a day of rapamycin. Rapamycin reduced the mortality rate from 42% to 20% and cut the average number of days patients were on a respirator from 33 days to 14 days.

LE: What is your experience with rapamycin?

Dr. Green: Personally, I’ve been taking 6 mg of rapamycin once a week since 2016. That’s an aggressive treatment. A more conservative treatment would be 3 mg once every 10 days.

My practice has been treating patients with intermittent rapamycin for over three years. We now have more than 500 patients. Rapamycin is a prescription drug and should be used under a doctor’s supervision. However, as regards prescription drugs, rapamycin is both safe and effective.

LE: What do you consider the strongest indication for rapamycin?

Dr. Green: To prevent or delay onset of Alzheimer’s disease in the 20% of population heterozygous for ApoE4 and for the 3% of population which is homozygous for ApoE4 and faces an 18-fold increased risk with onset 20 years sooner.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

Dr. Alan S. Green is a physician based in Little Neck, New York. He is an expert in the growing field of anti-aging medicine. Dr. Green earned his MD from N.Y. State University College of Medicine, Downstate Medical School in 1967.