A research team led by Dr. Cai at the Albert Einstein college of medicine have shown that stem cells in the hypothalamus influence how fast we age. The new research, shown in mice, may lead to approaches that delay or even prevent age-related diseases.
Unfortunately, like 70% of scientific research, this publication is behind a paywall, so those wishing to read will have to use the usual channels to obtain the publication. We discuss why paywalls are an unacceptable barrier to progress here in our interview with Sci-Hub.
So, what is the hypothalamus?
The hypothalamus (from the Greek ὑπό, “under” and θάλαμος, thalamus) is a part of the brain that performs a variety of functions. One of the most important functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland (hypophysis).
It has been known for a long time that the hypothalamus regulates important processes, including growth, development, sexual maturity, and metabolism. It has been known since 2013 that the hypothalamus also regulates aging throughout the body; this has lead some researchers to suggest it is one of the aging clocks that regulate lifespan.
Stem cell loss is one of the reasons we age
What is interesting about this new study is that the researchers have shown which cells in the hypothalamus are influencing aging. A small population of hypothalamic neural stem cells resides there and is responsible for creating new neurons in the brain.
The number of hypothalamic neural stem cells decline as we age, and this loss accelerates the aging process. Indeed, stem cell depletion is one of the hallmarks of aging and reserves of various types of stem cells dwindle not only in the hypothalamus but also in other tissues, so this is one part of a wider process.
However, the good news is there is a solution to this problem, replacing the lost stem cells periodically. The researchers found that loss of these stem cells accelerated aging but perhaps more excitingly they found this loss was not irreversible.
By replacing the stem cells or the molecules they create, it is possible to slow and even reverse some aspects of aging.
Determining if the hypothalamus is an aging clock
In order to see if these stem cells were regulating the aging process in some way, the research team began by looking at the fate of these cells as normal mice aged. The researchers observed that the mice started to lose hypothalamic stem cells at around 10 months of age – early middle age for a mouse; this was some months before the telltale signs of aging normally start to appear.
The researchers then tested to see if the gradual loss of stem cells was causing aging and not just a consequence of aging. To do this, they disrupted signalling in the hypothalamic stem cells in middle-aged mice. They observed that in these mice the aging process was significantly accelerated compared to the mice in the control group, which aged at the usual rate. The test mice died sooner than the control group due to this disruption.
Finally, the researchers wanted to know if adding replacement stem cells to the hypothalamus could reverse this particular hallmark of aging. To do this, they divided the mice into two groups, a group of middle-aged mice whose stem cells were destroyed, and a group of normally aged mice. They transplanted hypothalamic stem cells into the brains of both mouse groups and observed that in both groups the therapy significantly slowed the rate of aging and even reversed a number of measures of aging.
The research team found that hypothalamic stem cells seem to have an effect on the aging process by releasing molecules called microRNAs (miRNAs). The miRNAs are not involved in the creation of proteins by the cell but instead regulate gene expression. These miRNAs are contained inside very small particles known as exosomes, which the hypothalamic stem cells release into the cerebrospinal fluid.
Finally, the researchers made two mouse test groups again using middle-aged mice whose hypothalamic stem cells had been destroyed and normal middle-aged mice. They then extracted the miRNA-containing exosomes from hypothalamic stem cells and injected them into the cerebrospinal fluid of two mouse test groups.
Once more, the treatment significantly slowed down aging in both mouse test groups as confirmed by tissue analysis, endurance testing, muscle coordination, social behavriour and cognitive assessment.
The researchers’ next step is to identify the specific microRNAs and potentially other factors secreted by these stem cells that reverse aspects of the aging process. This would be the first step toward creating a therapy to potentially slow down the aging process to prevent some age-related diseases.
Finding ways to emulate the lost miRNA-containing exosomes and factors is interesting; however, in my view the better solution here is the one they tested first, the wholesale replacement of lost stem cells. Whilst stem cell replacement has a number of challenges, it would be the more robust and long-term solution rather than trying to prop up falling levels of miRNA-containing exosomes in a bid to compensate.
Given that the therapy increased lifespan by 10-15% in mice, it really highlights that this is only one of several damages that need to be addressed to bring the aging processes under medical control for the prevention of age-related diseases. Stem cell depletion in various stem cell populations in the body, not just in the hypothalamus, is a problem as we age; thankfully, progress in creating and mass-producing replacement stem cells is moving rapidly.
The repair-based strategies proposed by SENS and the Hallmarks of Aging paper are in my view the best way forward here. Whilst the research is very interesting, I would like to see more work in the replacement of these stem cells rather than trying to compensate for aging damage, which is the traditional approach of geriatrics and ultimately an approach that is doomed to failure.
 Yalin Zhang, Ph.D., Min Soo Kim, Ph.D., Baosen Jia, Ph.D., Jingqi Yan, Ph.D., Juan Pablo Zuniga-Hertz, Ph.D., and Cheng Han, Ph.D (2017).”Hypothalamic stem cells control ageing speed partly through exosomal miRNAs” Nature doi:10.1038/nature23282.