Nov
07
2020

Removal of Senescent Cells Can Extend Life

By | Inflammation, Mortality, telomeres

Several animal and human studies by the Mayo Clinic showed that removal of senescent cells can extend life. Researchers Xu et al. showed in 2018 that senescent cells weaken the body. Senescent cells are damaged cells that are still living. They can cause the release of inflammatory cytokines. The researchers showed in mouse experiments that intermittent senolytics increased life expectancy by 36%. Senolytics are drugs that dissolve senescent cells; the senolytic cocktail consisted of dasatinib plus quercetin.

In these mouse experiments their risk of dying was reduced by 65% compared to control mice that did not take senolytics.

Senescent cells causing premature aging

In the past 5 years research on aging and on chronic diseases made a lot of progress. Researchers realized that the accumulation of senescent cells is what causes both. All this happens because the process of apoptosis, the removal of dead cells, is impaired in the aging person. It appears that in older age there is a problem with dying cells and their removal. Instead they linger on and start producing cytokines, which cause inflammation. This can damage other cells and lead to organ failures. All this explains why older people often get chronic diseases and do not reach their normal lifespan. The accumulation of senescent cells also blocks regenerative factors that improve one’s health.

Senolytics

Dasatinib is a kinase inhibitor that was developed to treat acute myelogenous leukemia in adults and children. Researchers did animal experiments with a combination of dasatinib and quercetin for several years. They also have started smaller pilot clinical trials in humans. It appears that the human findings are very similar to the animal findings. But more research is needed to answer questions about side-effects and effects of removal of senescent cells.

Details about animal experiments with senolytics

The Mayo Clinic research showed that old mice treated with senolytics (dasatinib and quercetin) live 36% longer than controls that did not receive senolytics. Another part of this series of experiments showed that senescent cells are indeed what kills prematurely. They took senescent cells from old mice and transplanted them into young mice. Soon the young animals showed deterioration health wise and they died prematurely. Another control group were older mice that received senescent cells from old mice. They too died prematurely. Treatment with senolytics (dasatinib and quercetin) improved physical functioning and also survival.

Details about human trials regarding senolytics

For three days 11 participants received senolytics (dasatinib and quercetin). The effect of the drugs was evident for 11 days. The subjects took 100 mg of dasatinib daily and 500 mg of quercetin twice per day for 3 consecutive days. This dose was repeated twice more on a weekly basis for a total of 3 weeks. These patients had idiopathic pulmonary fibrosis. This is an incurable disease where senescent cells accumulate. These patients showed significantly improved gait speed, walking endurance, chair rise test performance and scores of other physical performances. All this occurred on day 5 after the initial dose of senolytics.

Alternative senolytics, so removal of senescent cells can extend life

Dasatinib as a senolytic has significant side effects.

For this reason, researchers looked for alternatives. Theaflavins, isolated from black tea fits this bill. It is non-toxic, but it is also effective as a senolytic. Researchers from Life Extension have developed a senolytic product containing theaflavins and quercetin. Instead of regular quercetin they included quercetin phytosome, which has 50-times more potent bioavailability. One capsule contains 74 mg of quercetin phytosome (the equivalent of 1250 mg of regular quercetin) and 275 mg of theaflavins.

Discussion

Future research needs to show whether or not the Life Extension senolytic indeed does what it promises. It claims that only one capsule per week stimulates apoptosis, reduces cytokines and increases longevity. I would like to see a clinical study that examines all these parameters. One measure of longevity is to determine the length of leukocyte telomeres. All the other laboratory tests are readily available. Research in this field will certainly continue and scientists will likely develop other senolytics.

Removal of Senescent Cells Can Extend Life

Removal of Senescent Cells Can Extend Life

Conclusion

The accumulation of senescent cells causes both aging and chronic diseases. Research showed that in older age the process of apoptosis, the removal of dying cells, is incomplete. As a result dying cells accumulate. They produce inflammatory cytokines, can damage other healthy cells and lead to chronic organ failure. In addition, cancer cells can develop and the patients can die prematurely. Senolytics are substances that clear out senescent cells. In mouse experiments they have already led to improved survival and health. Clinicians performed a clinical trial on patients with idiopathic pulmonary fibrosis, which is an incurable disease where senescent cells accumulate. They showed significantly improved gait speed, walking endurance, chair rise test performance and scores of other physical performances. One pill once per week with dasatinib and quercetin can achieve this. More research in this area can clarify why senolytics work and what the side effects are.

May
20
2017

Prevention Of Telomere Shortening

By | Alzheimer’s disease, breast cancer, Cancer, Cardiovascular disease, Dementia, depression, Diabetes, exercise, Inflammation, leukemia, lifestyle, lung cancer, Mortality, telomeres

Dr. Mark Rosenberg gave a talk on prevention of telomere shortening. This was presented at the 24th Annual World Congress on Anti-Aging Medicine (Dec. 9-11, 2016) in Las Vegas that I attended. The detailed title was: “The Clinical Value of Telomere Testing”.

What are telomeres?

Telomeres are the caps at the end of chromosomes. They are very important in the aging process. Prematurely shortened telomeres are linked closely to all major diseases like cardiovascular disease, cancer, diabetes and more. Telomeres are also a measure of the aging process. Aging occurs due to a decrease of the number of cells in organs and/or because of a lack of functioning of these organs. Telomeres get shortened every time a cell divides. But when the telomeres are used up, there comes a time when cells can no longer divide. These cells become senescent cells or they enter apoptosis (programmed cell death).

The senescent cells can become a problem when they get transformed into cancer cells and their telomeres lengthen again. These cancer cells divide rapidly and this can become the reason why cancer patients to die.

What is the significance of telomeres?

Telomere dysfunction is the first sign that the telomeres are getting shorter in a person compared to the average telomere length in a comparable age group. This is not only important for aging, but also has clinical implications. The shorter telomeres are, the higher the risk for cardiovascular disease. Telomere length also provides prognostic information about the mortality risk (risk of dying) with type 2 diabetes and for many cancers. Many physicians incorporate a telomere blood test into periodic health checks, if the patient can afford it.

Interventions that help telomere length

Here are a number of things we can do to lengthen our telomeres.

  1. Rosenberg mentioned that the strongest effect on telomere lengthening comes from caloric restriction and weight loss. 80 years ago they showed at the Cornell University that rats put on calorie restriction had a 30% increase in their mean and maximum lifespan. Many research papers have confirmed that the same is true in man and that the common denominator is telomere lengthening.
  2. Next are regular physical activity, meditation, reduction of alcohol consumption and stopping to smoke.
  3. Taking antioxidants and omega-3 fatty acids regularly will also lengthen telomeres.
  4. Improving one’s dietary pattern by adopting a Mediterranean type diet that contains cold-pressed, virgin olive oil.
  5. Telomerase activators. Here is some background on the TA-65 telomerase activator, which is based on Chinese medicine. A one year trial was completed with 250 units and 1000 units of TA-65 per day. The lower dose (250 units) showed effective telomere lengthening, while the placebo dose did not. The 1000 unit dose did not show statistical significance.

Should you wish to take TA-65, only take 250 units per day, not more.

Cancer and telomeres

There is a strong correlation between cancer and telomere shortening. When cells are at the brink of dying toward the end of their life cycle the telomeres get shorter and shorter. This is the point where the cells can turn malignant. Certain genetic abnormalities help the malignant transformation, like 11q or 17q deletions or a p53-dependent apoptosis response. Once cancer cells have established themselves they activate telomerase in 85% of cases. In the remaining 15% of cancer cases telomeres are activated through telomerase-independent mechanisms. Here are a few examples.

CLL

CLL stands for chronic lymphocytic leukemia. It is a disease of the aging population. At age 90 people’s bone marrow cells have a telomere length of only 50% of the length at birth. This is the reason that in older age CLL is more common. Researchers observed a population segment and found that the shorter telomeres were, the poorer the overall prognosis and overall survival for CLL was.

Lung cancer

Researchers examined the telomerase activity in patients with non-small cell lung cancer. When telomerase activity was present, the 5-year survival was only 55%. When telomerase activity was absent, the prognosis was 90% survival after 5 years.

Prostate cancer

  1. Prostate cancer risk correlated with telomere shortening in stromal cells. Men with shorter telomere length in stromal cells had a 266% higher risk of death compared to men with normal telomere length.
  2. Another study took blood samples and determined the telomere length in lymphocytes (the immune cells). Those men who came down with prostate cancer within a year after they had their blood sample, had short telomeres. The risk for prostate cancer in these patients was 355% higher than in the prostate cancer negative controls.

Yet another study looked at surgical tissue samples from 596 men that

Underwent surgery for clinically localized prostate cancer. Patients whose samples showed variable telomere lengths in prostate cancer cells and shorter telomeres compared to prostate samples with less variable telomere length and longer telomeres had a much poorer prognosis. They had 8-times the risk to progress to lethal prostate cancer. And they had 14-times the risk of dying from their prostate cancer.

Breast cancer

Breast cancer is diverse and consists of cases whose origins are genetic (BRCA1 and BRCA2), but there are also cases where the cancer is local or has a higher stage. In families with mutated BRCA1 and BRCA2 telomeres are significantly shorter than in spontaneous breast cancer. Increased telomerase activity in breast cancer cases is directly related to how invasive and aggressive the breast cancer is.

  1. In one study researchers analyzed blood leukocytes in 52 patients with breast cancer for telomere length  versus 47 control patients. Average telomere length was significantly shorter in patients with a more advanced stage of breast cancer than in early breast cancer. Mutated HER patients had the shortest telomeres. It follows from this that checking for the HER status and blood telomere testing adds to the knowledge of potential cancer development and prognosis.
  2. In patients with with larger breast tumors, more lymph node metastases and more vascular invasion the researchers found short telomere length of the cancer cells.
  3. More aggressive breast cancer cells have higher telomerase activity. More than 90% of triple negative breast cancers have short telomeres.

CNS disorders and telomeres

Dr. Rosenberg presented evidence for a correlation between shorter telomeres and the development of dementia. But dementias with Lewy bodies and Alzheimer’s disease are also linked to short leukocyte telomeres. The length of blood telomeres predicts how well stroke patients will do and how people with depression will respond to antidepressants.

Cardiovascular disease and telomeres

The renin-angiotensin-aldosterone system controls our blood pressure and keeps it constant. When this system is not stable, our blood pressure shoots up and causes cardiovascular disease. This is tough for the heart, as it has to pump harder against a higher-pressure gradient. A study of 1203 individuals was examining the connection between leukocyte telomere length and renin, aldosterone and angiotensin II activity. It concluded that oxidative stress and inflammatory responses affect the telomere length of leukocytes and that the more stress there is in the renin-angiotensin-aldosterone system, the more cardiovascular disease develops. The conclusion of the study was that the overall cardiovascular stress leads to shortening of leukocyte telomeres.

Prevention Of Telomere Shortening

Prevention Of Telomere Shortening

Conclusion

Telomere length testing from a simple blood test will become a more important test in the future as hopefully the cost comes down (currently about 300$). It can predict the general aging status by comparing a single case to the general telomere length of the public. But it can also predict the cancer risk, risk for mental disease and cognitive deficits (Alzheimer’s disease). In addition your cardiovascular status correlated globally with this test. What are the options for the patient, if the test comes back with short telomeres?

It allows you to change your lifestyle and adopt a healthy diet. You can exercise regularly, take antioxidants and meditate. There are even telomerase activators that are gradually becoming more known. They lengthen the telomeres. The cost of telomerase activators will likely still be a problem for some time. All in all telomere length tests are here to stay, but healthy lifestyle choices are the only tool for effective intervention at this point. This is good news: healthy lifestyle choices like non-smoking, exercise and avoiding non-processed foods are either free or have a reasonable price tag. Telomerase activators are big business and at this point not really affordable!

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Nov
19
2016

New Breast Cancer Cure?

By | breast cancer, Cancer

According to the popular press there is a new breast cancer cure. But we have to be careful with general statements like this. First of all, only 20% of breast cancers are HER2 positive. When the surgeon biopsies breast cancer, he sends the sample to the pathologist. Out of 100 samples, 20 come back with the finding that it is HER2 positive breast cancer.

Herceptin ® (trastuzumab), the first step of breast cancer cure

Trastuzumab is a monoclonal antibody that interferes with the HER2 receptor. Its main use is to treat HER2 positive breast cancers. But trastuzumab (brand name Herceptin ®) has serious side effects. In early HER2 positive breast cancer it can cause heart failure in 5.7–35.4% of patients, while it can cure breast cancer with a 35% cure rate of Her2-positive patients. It is significant to note that many of the studies used trastuzumab in combination with the chemotherapeutic agent anthracycline concomitantly. Anthracycline by itself has some cardio-toxic effect. Most of the studies that investigated heart toxicity of trastuzumab used this monoclonal antibody for 52 weeks. Newer studies show that as little as 9 weeks can be as effective in tumor cures, which reduces the risk of toxic effects on the heart to 2.2–2.3%.

Here is a link that shows visually what the effect of Herceptin ® may be on the HER2 surface marker in a woman with this type of breast cancer.

Lapatinib (Tykerb ® or Tyverb ®), the second step of breast cancer cure

Over-expression of oncogenic receptor tyrosine kinases inhibits the absorption of aging cancer cells, called apoptosis. These are proteins that normally function to remove dying cells at the end of their life span. In HER2 breast cancer these kinases are particularly common and are responsible for the cancer cell survival. Lapatinib is a dual tyrosine kinase inhibitor, which interrupts the HER2 and epidermal growth factor receptor (EGFR) pathways. In simpler terms, it removes dying cancer cells, so they cannot reactivate the cancer or allow cancer cells to survive.

A phase 3 clinical trial was done with Lapatinib and a chemotherapeutic agent, capecitabine (brand name Xeloda ®). With combination of  the two drugs there was a 51% reduction in the risk of the disease progression.

Herceptin ® and Lapatinib combined as new breast cancer cure

At the 10th European Breast Cancer Conference in Amsterdam professor Nigel Bundred reported about a trial involving 257 women with newly diagnosed, operable, HER2 positive disease. The researchers recruited these women between November 2010 and September 2015. The physicians took biopsies and the surgery followed within 2 weeks.

The trial had two parts: The physicians treated the first 130 women with trastuzumab (Herceptin ®) only, or lapatinib (Tyverb ®) only, for 11 days after diagnosis and before surgery. From other trials evidence became known that the combination of trastuzumab and lapatinib had better survival rates. The investigators decided to include a second part into their trial starting August 2013 with 127 women. Part of this trial was a combination treatment of trastuzumab and lapatinib.

Samples of tissue were taken from the original breast biopsies and then again two weeks later from the material of the breast surgery.

The pathologist examined the breast cells for a drop in the Ki67 protein, an indicator of cell proliferation. They also looked for an increase of apoptosis of 30% or more from the first date of the first biopsy. A “pathological complete response” was the term they used for a cure. When there was a partial cure, this was termed “minimal residual disease“. This meant that the tumor was less than 5 mm in diameter at the time of surgery. Women who had received the combination treatment had 11% pathological complete response (11% cure rate). 17% of the combination therapy group had minimal residual disease. There was no cure for those randomized to only trastuzumab and only 3% of that group had minimal residual disease.

New Breast Cancer Cure?

New Breast Cancer Cure?

Conclusion

Essentially this new research shows that two inhibitor drugs together are better than one or one in combination with conventional chemotherapy.

But we have to keep in mind that HER2 breast cancer includes only 20% of all types of breast cancer. When you hear that 11% of HER2 breast cancer was cured with the combination therapy in 11 days, it translates into only 2.2% of all types of breast cancer cured and only 3.4% of all breast cancer cases had minimal residual disease (tumor size less than 5 mm in diameter). This could be easily removed by surgery.

What everybody is excited about are the cures of 2.2% of all types of breast cancer (or 11% of HER2 breast cancer). This is a good start. But much more research is necessary to increase the number of cures. While we are seeing some progress for one group of breast cancer patients, it is not nearly sufficient to advertise this treatment as a “cure”.

For all breast cancers a more promising option is available. A study from Wayne State University, Detroit, Michigan has shown that cryoablation therapy for breast cancer without excision can give a much higher cure rate of 100% over a period of 1 ½ years. In this procedure the physician leaves the tumor in place. Cryotherapy (extreme local cold temperatures) kills the tumor cells. It gives a cosmetically superior result. The FDA accepted this alternative treatment protocol, but cancer experts are slow to accept it.