Cell Aging, Death, and the Naked Mole Rat

A shocking truth: We age the more we get injured? The secret of the naked mole rat’s longevity lies within it’s resistance to inflammation.

How is it that pathogens such as viruses and bacteria cause infections and how does the body fight them off? Let’s start from the basics. Then, we will explain the interesting ways in which the immune system works and how it is structured.

Today, we will talk about aging. Why do we age? Is there anyway to slow aging? We will explain the various barriers that the immune system tries to overcome due to aging from the viewpoint of the immune system.

Cell aging and death… due to aging, old cells begin to accumulate

Death is an inescapable fact of life for us. We all want to live a long healthy life, enjoying it right up until the time we die, don’t we? However, the fact is that due to illnesses such as cancer, infections, or dementia, the quality of life in our twilight years will no doubt decrease.

So why do we age? Even if we cannot go back to being young, is there no way to slow the decline in our mobility or ages related disabilities? Today, these problems are being tackled from various angles by researchers.

According to one theory, ‘due to aging, old cells begin to accumulate within our organs. Because of this, they begin to malfunction. This is the real identity of aging.’. The following paragraphs go into the aging of cells, but for now we will explain the removal of these aged cells.

In 2011, a shocking announcement was issued: scientists developed mice in which we could remove aged cells through genetic engineering. Through this, they were able to restrain changes that came with aging such as loss of muscle. Additionally, they reported that through this same process, they were able to delay the onset of illnesses that came with aging thus lengthening the lifespan of the rats.

In 2015 according to Professor James L. Kirkland, the use of a drug that combines a type of anti-cancer drug and a kind of naturally occurring polyphenol called quercetin, enabled the selective removal of these aged cells, known as senolysis.

Recently, a group led by Professor Makoto Nakanishi of Tokyo University revealed a new process that through the use an inhibitor could selectively remove aged cells by targeting the glutamin metabolic enzyme 1 (GLS1) that is produced especially by them.

We can de-age by removing old cells with antibodies?

Experiments involving the use of antibodies to remove aged cells are also being vigorously conducted. Abnormal proteins being made by cancer cells bond to MHC (Major Histoacompatability Complex) as a cancer antigen and then present as a cancer cell. It is also thought that these abnormal proteins are also produced within aged cells, presenting as ‘Aging antigens’ on the surface of these aged cells.

Professors of Juntendo University including Professor Tohru Minamino observed proteins called GPNMB presenting on aging endothelial cells of blood vessels and have shown that the use of antigens could be used to target the GPNMB and remove these aging cells, turning back the clock on these blood vessels in mice.

Furthermore, Professor Minamo et. al. have thought of a way to make mice produce the GPNMB antigens themselves.  They developed a vaccine by mixing GPNMB to an adjuvant and administered this to the mice. Following this, cell aging brought upon by GPNMB antigens were eliminated and various symptoms brought about by aging were also improved.

All of this is still only in the stage to be used on mice, however, this result hold hope that one day in the near future, a similar vaccine can be developed to slow the process of aging in humans.

Moving on, how do we go about removing the aged cells in younger people?

Cancer cells are disposed of by immune cells, and it is thought that aged cells too are disposed of by our immune system. To put it simply, as we age, our immune system ages with us. It is thought that as we age, our ages immune system struggles to keep up with the disposal of aging cells.

Why do cells age?

Aged cells are ones that stop multiplying and no longer respond to stimuli. But how do cells age in the first place?

Cells have a lifespan, and in order to make up for the cells that have died in each group, stem cells divide and mature into the necessary type. Every time a cell divides, DNA is replicated but errors can occur during this stage.

At the ends of each chromosome is a special structure of DNA called a telomere which gets shorter every time it divides. If a telomere becomes too short, problems can occur in DNA replication. In the case of reproducing somatic cells in animals, if the limit to the number of divisions is exceeded, replication will begin to stop. In humans, this limit is about 50 times. This is known as the Hayflick limit, and it is suspected that it is the cause of the shortening of telomeres and the replication of damaged DNA.

Like the liver’s hypatocytes, there are cells which have long lifespans and rarely divide. Even in these cells though, damage to the DNA can occur via radiation, ultraviolet light, free radicals originating from the mitochondria (oxidative stress) or free radicals from white blood cells during inflammation.

There are lots of enzymes that can restore the damage dealt in such cases but if this restoration doesn’t happen in time, mutations can occur which are connected to the appearance of cancer cells.

There is an animal resistant to mutations?!

If DNA is damaged, a molecule called P53 becomes incited. P53 instruct molecules called P16 and P21 to stop cell cycles. This function stops cancer cells developing by stopping the multiplication of mutations that occur from damaged DNA that couldn’t be restored. This cannot stop the damage or the mutation of DNA however.

Recently, it has been reported that there has been research into the intestinal cells of animals, the mutation of their DNA and its relation to the lifespan of the animal. To put the results frankly, animals that have a higher rate of mutation to somatic cells have the shortest lifespans.

As they age, mutations accumulate in animals whose cells are more prone to mutations. As such, their lifespans are shorter. It is thought that in aged cells, DNA damage and replication errors occur the same way as cancer cells do and as the animal ages, the more of these cells they have.

The naked mole rat doesn’t age and has low rates of cancer

In this thesis a deeply interesting animal was brought up. The naked mole rat. This rat lives in holes it dug in the savannas of Africa and are rodents about the same size as a mouse.

As opposed to the mouse, whose lifespan is about 3 years, the longest lifespan of an observed naked mole rat was over 37 years. It is known that ailments related to aging such as cancer are harder to occur in naked mole rats. It is also known that the rate of accumulation of cell mutation is low in these animals.

So why do naked mole rats have so few mutations? A group led by Professor Kyoko Miura of Kumamoto University gave carcinogenic chemicals to both mice and naked mole rats and examined the frequency of cancer causation aswell as the condition of their tissue. The results showed that within half a year, nearly all of the mice developed cancers whilst in comparison, over 2 years not one instance of cancer was found in the naked mole rats.

The large difference between both is that after the administration of the chemicals, the inflammation at the site of injection presented differently. Compared to the mice, they found that the inflammation was light and kept in check by the naked mole rats. From this, we can learn that inflammation works to the promote the development of cancer. Why is it that inflammation does not occur as strongly in naked mole rats?

Miura’s team researched/looked into the naked mole rat's' genetics (code) and discovered that the genetic code which causes cell death (which acts as a trigger for inflammation) was lacking functionality. In other words, it is thought that excessive inflammation can promote the occurrence of cancer and thus shorten one’s lifespan.

The immune system’s ‘surveillance system’ in disposing of aged cells

               However, the immune system within us contains a surveillance system. Immune cells such as the killer T-Cell and the natural killer cell detect not only cancer cells but also aged ones. These cells kill and dispose of the damaged cells before they grow. If this function weakens, aged cells begin to accumulate around your body, shortening your lifespan.

In actuality, aged cells exhibit aging antigens on the MHC. Killer T cells recognise this and then attack. Furthermore, it is known that aged cells also secrete a variety of inflammatory cytokine. This is called senescence-associated secretory phenotype (SASP).

It is reported that aged cells also give off a factor that stimulates the NK cells, cause them to be disposed of by them, exactly like a cell with a viral infection. To summarise, aged cells are disposed of in the same way that a foreign body would be.

(Further) it is thought that as the immune system becomes weaker with age, old cells accumulate leading to the aging of one’s organs, subsequent loss of function and is connected to an individual's eventual death.

Returning to the alternative method of aged cell disposal previously mentioned, Nakanishi’s team discovered that some aged cells that expresses the protein p16, an indicator of aging also expresses PD-L1. PD-L1 is a molecule that switches on the brake molecule PD-1, suppressing the activation of T-cells.

They also discovered that aged killer T-cells also strongly express PD-1. We know that if an aged cells PD-L1 switches on a killer T-cell’s PD-1 molecules, the killer T-cell halts. For this reason, it is suspected that aged killer T-cells cannot effectively dispose of the body’s other aging cells.

Administration of Anti PD-1 Antibodies supresses aging

The fact that killer T-cells expressing PD-1 were unable to eliminate aged cells expressing PD-L1 was discovered during in vitro experiments.

At the time, Nakanishi’s team administered the drug Opdivo, an anti-PD-1 antibody used in immunotherapy. Once administered, the killer T-cells were able to kill the PD-L1 expressing aged cells as predicted. They confirmed this to be effective within mice too with the administration of Opdivo resulting in the effective disposal of aged cells. The administration of Opdivo in elderly mice saw an increase in their grip strength, improvement in symptoms of fatty liver and other such lifestyle diseases, proving an across-the-board anti-aging effect.

There are side effects of Obdivo which include auto-immune disorders as well inflammation amongst others. In order to use this in humans, it is necessary to careful investigate the appropriate dosage to restore the function of disposal of aged cells. It is also said that the elderly often have a lower response to immune checkpoint inhibition therapy due to the aging of T-cells.

There is still a big hurdle to overcome in order to use this in clinics, but Nakanishi’s team’s experiments have shown that the immune system, especially with killer T-cells, is able to dispose of aged cells and can rejuvenate the body to this level hold great significance and shows the possibility of one day stopping the process of aging.

Translation by Ronnie Dickson


 Source: 驚愕の事実「傷つけてばかりいる」と老化する…！「ハダカデバネズミ脅威の長寿力」の秘密は炎症を起こさない仕組みにあった！（現代ビジネス） - Yahoo!ニュース