Loss of TIMP1 and TIMP3 Maintains Youthful Stem Cell Activity in Aging Mice

Stem cell activity declines with age, an evolutionary trade-off that reduces the risk of death by cancer at the cost of increasing frailty and a slower death due to failure of tissue maintenance. This is just one of the many contributing factors that together determine the present human life span and the course of failing health for most people. Researchers would like to be able to restore youthful stem cell activity in old people without significantly increasing the risk of cancer, as continued tissue maintenance would greatly reduce the impact of aging and incidence of age-related disease.

At present this line of work is still in the comparatively early stages: much of the research community involved is searching for the signals and mechanisms responsible for stem cell decline, changes in the tissue environment that are most likely reactions to rising levels of cellular and molecular damage produced over the course of aging. Some points of potential intervention have been found in recent years, such as altering levels of GDF-11 to improve stem cell function in aged mice. Here is news of another potential basis for therapies, discovered by chance during cancer research:

Think of tissue as a building that is constantly under renovation. The contractors would be metalloproteinases, which are constantly working to demolish and reconstruct the tissue. The architects in this case, who are trying to reign in and direct the contractors, are known as tissue inhibitors of metalloproteinases - or TIMPs. When the architect and the contractors don't communicate well, a building can fall down. In the case of tissue, the result can be cancer. To understand how metalloproteinases and TIMPs interact, medical researchers bred mice that have one or more of the four different types of TIMPs removed. The team examined the different combinations and found that when TIMP1 and TIMP3 were removed, breast tissue remained youthful in aged mice.

In the normal course of aging, your tissue losses its ability to develop and repair as fast as it did when you were young. That's because stem cells, which are abundant in your youth, decline with the passing of time. The team found that with the TIMP1 and TIMP3 architects missing, the pool of stem cells expanded and remained functional throughout the lifetime of these mice. "Normally you would see these pools of stem cells, which reach their peak at six months in the mice, start to decline. As a result, the mammary glands start to degenerate, which increases the risk of breast cancer occurring. However, we found that in these particular mice, the stem cells remained consistently high when we measured them at every stage of life." The team also found that despite large number of stem cells, there was no increased risk of cancer. "It's generally assumed that the presence of a large number of stem cells can lead to an increased cancer risk. However, we found these mice had no greater predisposition to cancer." The next step in this research is to understand why this is happening.

Link: http://medicine.utoronto.ca/news/breast-cancer-research-uncovers-fountain-youth

Comments

Further evidence that Epigenetic intervention offers a route towards rejuvenating the aging system. It is good they are finding out all the pro aging and pro youthful factors, it will take a long time to do so but eventualy they will work it all out.

Blood factors can restore the system to a younger phenotype and address a number of damage types. Studies so far have shown DNA repair, Mitochrondrial function improved, Stem Cells returned to function, improved injury repair, some repair to the ECM matrix and various other positives. Its obviously even of interest to SENS as they are funding research into it!

Honestly I think Factors aka Epigenetic control could and does work in harmony with SENS as it is addressing some of the damage types outlined. Will it fix everything? No of course not but its a very compelling start which has shown impressive results far beyond any other age reversal approach.

I think the emerging Senescent cell removal technology we are seeing lately would be a very good combined therapy in conjunction with Epigenetic control. Not to mention that a rejuvenated system can and would start clearing house using its own systems again too.

Identying the myriad factors is of course a very long term project unless BigPharma with its industrial assays begins looking. If the Wyss-Corey Plasma study pans out that may well happen, the world and his wife will be working on identifying the factors.

The most accesible way currently is to use Plasma and if what Dr Wagers hinted could be the case exposure to factors may well have a lasting effect after a period of treatment. It may well be possible given sufficient exposure to restart the system, including Endocrines which would then resume secretion of youthful factors themselves. We have certainly seen the Liver restored in mice within 5 weeks exposed to plasma which is part of the Endocrine system, good reason to suspect the rest would follow suite.

For what its worth I believe aging is a hybrid of accumulated damage which then reaches the point that it begins to destablise the system Epigenetically and the downward spiral begins. I think rejuvention using factors/plasma is an approach that could definately work with SENS rather than being mutually exclusive.

It is very interesting indeed to see no increase in cancer here having aged stem cells carry on working.

Posted by: Steve H at April 9th, 2015 8:29 AM

It is interesting that increased cancer rates were not seen with an increase in stem cell activity. Perhaps the declining function of stem cells with age is not an anti-cancer mechanism, but is just a production of evolutionary neglect as by the time declining stem cell function has an impact a wild mouse would probably be dead anyway.

It would have been interesting to see if boosting stem cell function had an impact on mouse lifespan. But this probably wasn't investigated due to the 3 or so length of that experiment.

Posted by: jim at April 9th, 2015 10:08 AM

@Jim

The decline of Stem cell function is very much to do with the local phenotype of it's Cell niche, once that becomes aged the cells cease working properly or shut down. Irina Conboy mentions this in her recent "Beyond Parabiosis" video.

Inversely aged Stem cells introduced to a young phenotype resume function and according to Wagers DNA damage from daughter cells was not observed. This suggests that it is more than simply forcing damaged biology into working again.

You are also right about lifespan I think there is a good chance of some increase albeit small. The Cancer rate is very interesting indeed though as one of the fears of awakening dormant Stem Cells is increasing Cancer, that is seemingly not the case nor has it been in other rodent experiments.

Posted by: Steve H at April 9th, 2015 11:04 AM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.