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15th March 2015

New class of drugs could slow the aging process in multiple ways

A new class of drugs known as "senolytics" has been shown to increase the healthy lifespan of mice. Not only that, but multiple different aspects of the aging process can be improved simultaneously.

 

lab mouse

 

In multicellular organisms, including humans, cell division is essential for growth, development and repair. The average person will experience approximately 10,000 trillion cell divisions in their lifetime. As we age, our cells become less capable of dividing. Like a VHS tape being copied over and over again, the process of bodily growth and renewal is less and less accurate. The resulting errors contribute to disease and ultimately death.

Cells that have stopped dividing are known as "senescent" cells. Over time, they accumulate inside us and cause aging. They are similar to cancer cells – in that they can resist apoptosis (programmed cell death). Normally, between 50 and 70 billion cells die each day in an adult. This form of cell suicide helps to maintain a healthy equilibrium, or homoeostasis, ensuring an appropriate number of cells in the body is maintained. With senescent cells, however, this balance is disrupted. The build-up of senescent cells results in side effects, including the production of harmful chemicals. The situation can worsen dramatically if a cell's DNA has been seriously damaged – leading to out-of-control cell growth and cancer, or neurodegenerative disorders.

This week, a study was published in the journal Aging Cell, by researchers from The Scripps Research Institute (TSRI) and Mayo Clinic. They describe a new class of drugs known as "senolytics", which can selectively kill senescent cells – potentially restoring the balance of cell numbers. Two compounds were identified as candidates for testing, both found in existing medications. In Petri dish cultures, they produced the following results:

 


 
  Compound name   Description   Target location and result  

 
  Dasatinib   Cancer drug, used mainly for leukaemia, and marketed under the name Sprycel.   Senescent human fat cell progenitors were eliminated.  

 
  Quercetin   A natural compound found in various fruits, vegetables, leaves and grains. Sold as a supplement that acts as an antihistamine and anti-inflammatory.   Senescent human endothelial cells (found on interior surface of blood vessels) were eliminated.  

 

 

Individually, each compound was effective at removing the senescent cells in these locations, without damaging other cells. When combined together, however, the researchers observed even greater effects. Following the Petri dish experiments, a cocktail of both compounds was administered to mice in old age. The results were remarkable.

“In animal models, the compounds improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended healthspan,” comments Laura Niedernhofer, PhD, in a press release from TSRI. “Remarkably, in some cases, these drugs did so with only a single course of treatment.”

FutureTimeline.net contacted the study authors to request more specific details. We received the following information regarding the mouse tests:

 


 
  Test number   Test conditions   Results  

 
  1   One leg of each mouse was irradiated with ionising radiation to lower their exercise endurance by 30-50%.   • Animals given a single dose of the senolytics recovered full exercise endurance within five days.
• Four months later, unmedicated mice were still 15% below normal endurance levels, while mice treated with senolytics retained their full exercise endurance.
 

 
  2   This test looked at the heart function of normal aged mice equivalent to 65-year-old humans. For context, left ventricular ejection fraction (LVEF) is typically reduced when valves stiffen with age or the heart muscle is damaged.   • A single dose of senolytics increased LVEF by ~10%.
• A single dose of senolytics also improved how blood vessels in the old mice responded to vasodilators (drugs used for the treatment of hypertension) by 10-15%.
 

 
  3   Mouse model of a human disease of accelerated aging   • Periodic treatment of the mice with senolytics led to a delay in the onset of age-related symptoms including unstable gait, hunched posture and trembling, for in some cases up to several weeks. Each week in the life of the progeroid mice is equivalent to 3-4 years in human life.
• Healthspan, the period of "healthy living", was extended by roughly 10%.
• Bone mineral density (a measure of osteoporosis) was improved by more than 15%.
• An index of vertebral health for avoiding lower back pain was improved by 20%.
• Brain and neurological dysfunction were also alleviated.
 

 

 

“We view this study as a big, first step toward developing treatments that can be given safely to patients to extend healthspan or to treat age-related diseases and disorders,” says Professor Paul Robbins, PhD, also from the Scripps Institute. “When senolytic agents, like the combination we identified, are used clinically, the results could be transformative.”

“The prototypes of these senolytic agents have more than proven their ability to alleviate multiple characteristics associated with aging,” said Mayo Clinic Professor James Kirkland, MD, PhD, senior author of the new study. “It may eventually become feasible to delay, prevent, alleviate or even reverse multiple chronic diseases and disabilities as a group – instead of just one at a time.”

"Senescence is involved in a number of diseases and pathologies, so there could be any number of applications for these and similar compounds," concludes Professor Robbins. "Also, we anticipate that treatment with senolytic drugs to clear damaged cells would be infrequent, reducing the chance of side effects."

 

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