February 04, 2016

Scientists extend life of mice by 35 per cent by removing accumulated cells that no longer divide with compound AP20187

Researchers at Mayo Clinic have shown that senescent cells – cells that no longer divide and accumulate with age – negatively impact health and shorten lifespan by as much as 35 percent in normal mice. The results, which appear today in Nature, demonstrate that clearance of senescent cells delays tumor formation, preserves tissue and organ function, and extends lifespan without observed adverse effects.

“Cellular senescence is a biological mechanism that functions as an ‘emergency brake’ used by damaged cells to stop dividing,” says Jan van Deursen, Ph.D., Chair of Biochemistry and Molecular biology at Mayo Clinic, and senior author of the paper. “While halting cell division of these cells is important for cancer prevention, it has been theorized that once the ‘emergency brake’ has been pulled, these cells are no longer necessary.”

The immune system sweeps out the senescent cells on a regular basis, but over time becomes less effective. Senescent cells produce factors that damage adjacent cells and cause chronic inflammation, which is closely associated with frailty and age-related diseases.

Senescent cells are important because they prevent cancer spreading by stopping cell division and when people are young they are regularly cleared out of the body before they can cause problems.

As we age the body stops being able to get rid of the dead cells as quickly and they can build up, stopping new cells regenerating.

Now scientists have shown that mice who received a special compound to clear out the senescent cells lived 35 per cent longer than those allowed to age normally. They were also stronger and healthier for longer.

If the same effects could be replicated in humans it could mean people living for decades longer, and in much better health.

First author Dr Darren Baker, a molecular biologist at Mayo Clinic, is optimistic about the potential implications for humans.

"The advantage of targeting senescent cells is that clearance of just 60-70 percent can have significant therapeutic effects,” he said.

he clearance of senescent cells also delays tumour formation, preserves tissue and organ function, and extends lifespan without any adverse effects.

The mice also looked healthier and had less inflammation in fat, muscle and kidney tissue.

Researchers used a compound called AP20187 to trigger genes into ramping up their removal of senescent cells.

"Senescent cells that accumulate with aging are largely bad, do bad things to your organs and tissues, and therefore shorten your life but also the healthy phase of your life," says Dr. van Deursen.

“And since you can eliminate the cells without negative side effects, it seems like therapies that will mimic our findings - or our genetic model that we used to eliminate the cells - like drugs or other compounds that can eliminate senescent cells would be useful for therapies against age-related disabilities or diseases or conditions."

Other scientists are also working towards anti-ageing therapies and a trial in the US to test the diabetes drug metformin are due to start later this year.

Prof Ilaria Bellantuono, Professor of Musculoskeletal Ageing, University of Sheffield, said: “This work is interesting because it confirms some of the findings from a previous study, which used mice with accelerated ageing, using mice which are ageing naturally. It shows improved health in some aspects of their ageing such as reduced incidence of cancer, cataracts, and improved memory, suggesting that removal of these aged cells can be beneficial.


Clearance of senescent cells prolongs healthspan.


Nature - Naturally occurring p16Ink4a-positive cells shorten healthy lifespan





Abstract

Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16Ink4a (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16Ink4a-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan

Accumulation of cells that no longer divide is one of the seven causes of aging which are targeted by SENS

The SENS Research Foundation’s strategy to prevent and reverse age-related ill-health is to apply the principles of regenerative medicine to repair the damage of aging at the level where it occurs. We are developing a new kind of medicine: regenerative therapies that remove, repair, replace, or render harmless the cellular and molecular damage that has accumulated in our tissues with time. By reconstructing the structured order of the living machinery of our tissues, these rejuvenation biotechnologies will restore the normal functioning of the body's cells and essential biomolecules, returning aging tissues to health and bringing back the body’s youthful vigor.

The AP20187 work relates to ApoptoSENS.

Our cells have built-in programming that sometimes veers them far away from their normal fate. Some of this programming watches out for conditions emerging within the cell that could put the rest of the body at risk; similar systems exist because the body no longer has need for the function that the cell normally fulfils. Pushing these cells to undergo such transformations is favored by evolution because it meets short-term needs, and having a few of these abnormal cells in the body for is nearly harmless. But the number of these cells in our tissues gradually rises over time, until by our fifth decade or so they begin to reach levels that are harmful to normal tissue function.



Classic Senescent Cells

The original and most well-studied sort of cells of this type are what are usually called “senescent” cells. Senescent cells began their existence skin cells, or as related cells that normally play supporting roles in other organs, but were forced into an abnormal state where they lost the ability to divide and reproduce themselves as a protective response to some danger. For instance, the senescence program is activated in cells that undergo risky changes in their DNA expression that put them on a path toward becoming cancerous; it is also activated in some cells involved in the wound response, to keep them from overstepping their bounds and generating an overgrowth of fibrous connective tissue.

But in addition to halting growth, senescent cells secrete abnormally large amounts of proteins that inflame the immune system and degrade the normal supporting tissue architecture. The relatively small number of such cells in a youthful tissue is so small as to be harmless, but after decades of accumulation, the number becomes large enough that their abnormal metabolic state begins to pose a threat to surrounding, healthy tissues. Larger numbers of senescent cells in a tissue make it more vulnerable to the spread of cancer, contribute to inflammation, and skew the local activity of the immune system.

Cells in Fat Tissue

It’s well-known that people lose muscle mass as part of the degenerative aging process; it’s much less understood that fat mass, too, begins to decline in the fourth decade, albeit more slowly – and it’s a decline that can’t be explained just by reduced energy intake. But the process is uneven, leading to relative increases in fat tissue in some places even as other places lose nearly all of their fat. In the process, fat tissue begins to behave abnormally, releasing large amounts of signaling molecules that cause inflammation and make the body more resistant to the hormone insulin. These age-related abnormalities then drive a range of unhealthy metabolic changes, including a reduced ability to move blood sugar out of the blood in response to the hormone insulin.

But the the reasons why fat tissue goes haywire during degenerative aging do not lie in the fat cells per se (adipocytes – the ones that store up excess Calories). Instead, the culprits are two other kinds of cells that reside in fat tissue: preadipocytes and visceral adipose tissue macrophages (ATMs). Preadipocytes are the precursor cells from which fat cells are formed. They begin to behave abnormally in all people during degenerative aging, whether they are slim or overweight: their expression of their genes becomes altered; they release more inflammatory factors; and they fail to reproduce themselves and to develop into mature fat cells, which may be one reason why the level of unhealthy free fatty acids circulating in the blood rises with age. Aging preadipocytes also develop a large droplet of abnormally-stored fat molecules within themselves, which may be part of why they and their progeny become more insulin resistant than the corresponding cells in young people’s fat tissue.

The other unhealthy change in that occurs in fat tissue over time occurs in the so-called visceral fat – the fat tissue that surrounds the gut and liver. It’s become widely understood that most of the metabolic harm that occurs as a result of obesity is the result of having too much fat in the visceral depot in particular (making people “apple-shaped” rather than “pear-shaped”). The degenerative aging process leads to a higher percentage of one’s total fat being shifted into the visceral fat tissue, as well as into aberrant storage in the muscles and the liver.

It’s less well-appreciated that the reason why excess visceral fat is so metabolically toxic is that it causes the accumulation of a kind of immune cells called adipose tissue macrophages (ATMs) to multiply in the visceral fat tissue. This may be an attempt by the immune system to clean up the wreckage from bloated, dying fat cells when excessive amounts of energy are stuffed into the local adipocytes and the has a harder time providing an adequate blood supply. Like senescent preadipocytes, ATMs are also highly inflammatory cells, and their accumulation in visceral fat is probably one key reason why obese people become insulin resistant even when they have not yet undergone other degenerative aging changes. It is also possible that degenerative aging itself has effects on the function of ATMs that go beyond those attributable to the sheer mass of visceral fat and number of ATMs in the tissue.

Immune Cells
CD8+ T-cells (or killer T-cells) are a kind of immune cell that specializes in destroying cells that have been hijacked by viruses or by cancer. Killer T-cells first emerge as naïve cells that are out on the lookout for entirely new threats, but in order to do their job, they must assume a specialty, being trained by other immune cells to recognize, seek out, and eliminate a very particular threat. But while the total number of invaders that the body has encountered increases with every year of life, the total number of killer T-cells cannot: the sum total of all the different specialized cells, plus the naïve cells, is held constant over time. So an increase in the number of killer T-cells with one particular specialization can only come at the expense of a decrease in cells with different specializations (and naïve cells) .

As part of the degenerative aging process, an imbalance in the killer T-cell population occurs. Specific subsets of killer T-cells refuse to cull their numbers to make room for other subsets, and instead begin to occupy more and more of the limited immunological “space” – literally crowding out cells that are equipped to fight other infections. This crowding-out effect is thought to be one of the main reasons for the weakened immune responses of people as they age, which is why so many people over the age of 65 die or are hospitalized each winter by influenza or pneumonia, while younger people can bounce back after a couple of days in bed. This crowding-out effect is also one reason why vaccines are less effective in older people than in younger: there are fewer naïve cells available for the vaccine to “teach” to recognize the new threat.

The Solution

Each of these various kinds of abnormal cells occur in different tissues, and the problems they cause are distinct from one another. Still, the same basic strategy can be used to eliminate the harmful effects of all of them, which is to destroy the cells themselves. There are two main approaches that could be used to achieve this:


  • Develop a drug that is toxic to the unwanted cells, or that makes them commit suicide, but that doesn't harm healthy, normal cells; or
  • Stimulate the immune system to selectively seek out and kill the target cells.

SOURCES - Mayo Clinic, Telegraph UK, Nature, SENS Research

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