Loss of Neural Stem Cells in the Hypothalamus Influences the Pace of Aging

A few years back, researchers found that manipulating levels of NF-κB in the hypothalamus influenced the pace of aging in mice. That work was several steps removed from any idea as to what exactly was going on under the hood; changing the amount of a specific protein in circulation can have any number of effects, both direct and subtle. NF-κB is already an area of interest in the study of aging and metabolism, and so there are many mechanisms to speculate on in this context. There was indeed speculation at the time. Other indirect evidence suggests that the quality of cellular function in the hypothalamus is connected to the pace of aging, such as results arising from investigations of autophagy and its relevance in this part of the brain. Other researchers have made some inroads into mapping possible ways in which the hypothalamus might influence the operation of metabolism throughout the body in order to modestly speed or slow aging. It is well known that the hypothalamus regulates all sorts of aspects of metabolism, but the open question is which of these relationships are relevant to the matter at hand.

The team that investigated NF-κB in the hypothalamus has since been hard at work, seeking a better understanding as to why this part of the brain is important in the way in which metabolic processes determine individual variations in aging and longevity. In a recently published paper, the team now points to one particular small population of stem cells in the hypothalamus that diminishes with age; losing these cells more rapidly appears to speed processes of aging throughout the body. The researchers believe that signals generated by these cells are the mechanism of action, and a closer investigation of these signals is the next step in this line of research. It has to be said that this sounds quite similar to the situation for Parkinson's disease, at least at the high level, in which one small but critical population of cells in the brain is diminished at a different pace in different individuals, and where autophagy - and disruption of autophagy in aging - might be important in determining the rate of loss. It also clearly parallels what is known of the age-related decline of stem cell populations in all tissues. We become damaged, and stem cell loss and inactivity is a downstream consequence of that damage.

Either way, this might make an interesting target for cell therapy: certainly, replacement of stem cell populations is on the rejuvenation research checklist. Whether it is a priority in this case rather depends on the size of the effect, however, which in this study looks like a ~10% gain in life expectancy resulting from a single cell therapy treatment carried out in middle-aged mice. Unfortunately, significant changes in longevity in mice on the basis of altered metabolism so far do not translate to significant changes in longevity in humans, at least in the few areas where the data exists for comparison. The life spans of short-lived mammals are far more plastic in response to circumstances and interventions than those of long-lived mammals. In the case of stem cell replacement as a way to reverse declines, however, it is hard to say how the comparisons will turn out - the data just isn't there yet. It is the fond hope of many in our community that approaches based on repairing loss and damage, very different from approaches based on altering metabolism to modestly slow damage accumulation or resist the consequences of damage, will turn out to have similarly scaled effects on life span in mice and humans. Maybe so, maybe not. As I said, the data isn't there. In order to find out, rejuvenation therapies based on repair must be rigorously tested in humans, and that hasn't yet happened in any useful way, even in the stem cell field.

Brain Cells Found to Control Aging

The hypothalamus was known to regulate important processes including growth, development, reproduction and metabolism. In a 2013 paper, researchers made the surprising finding that the hypothalamus also regulates aging throughout the body. Now, the scientists have pinpointed the cells in the hypothalamus that control aging: a tiny population of adult neural stem cells, which were known to be responsible for forming new brain neurons. "Our research shows that the number of hypothalamic neural stem cells naturally declines over the life of the animal, and this decline accelerates aging. But we also found that the effects of this loss are not irreversible. By replenishing these stem cells or the molecules they produce, it's possible to slow and even reverse various aspects of aging throughout the body."

In studying whether stem cells in the hypothalamus held the key to aging, the researchers first looked at the fate of those cells as healthy mice got older. The number of hypothalamic stem cells began to diminish when the animals reached about 10 months, which is several months before the usual signs of aging start appearing. "By old age - about two years of age in mice - most of those cells were gone." The researchers next wanted to learn whether this progressive loss of stem cells was actually causing aging and was not just associated with it. So they observed what happened when they selectively disrupted the hypothalamic stem cells in middle-aged mice. "This disruption greatly accelerated aging compared with control mice, and those animals with disrupted stem cells died earlier than normal." Could adding stem cells to the hypothalamus counteract aging? To answer that question, the researchers injected hypothalamic stem cells into the brains of middle-aged mice whose stem cells had been destroyed as well as into the brains of normal old mice. In both groups of animals, the treatment slowed or reversed various measures of aging.

The researchers found that the hypothalamic stem cells appear to exert their anti-aging effects by releasing molecules called microRNAs (miRNAs). They are not involved in protein synthesis but instead play key roles in regulating gene expression. miRNAs are packaged inside tiny particles called exosomes, which hypothalamic stem cells release into the cerebrospinal fluid of mice. The researchers extracted miRNA-containing exosomes from hypothalamic stem cells and injected them into the cerebrospinal fluid of two groups of mice: middle-aged mice whose hypothalamic stem cells had been destroyed and normal middle-aged mice. This treatment significantly slowed aging in both groups of animals as measured by tissue analysis and behavioral testing.

Hypothalamic stem cells control ageing speed partly through exosomal miRNAs

Although the nervous system clearly has a role in ageing, and research has demonstrated that the hypothalamus is particularly important, the cellular mechanism responsible for ageing is still unknown. It has been shown that adult neural stem/progenitor cells (NSCs) reside in a few brain regions that mediate local ­neurogenesis and therefore several aspects of brain functioning. Studies on adult neurogenesis have focused on the hippocampus and the sub-ventricular zone of the lateral ventricle in the brain. Decreased neurogenesis in these regions often correlates with the advent of related ageing-­associated disorders. More recently, it has been shown that adult NSCs are present in the hypothalamus, in particular in the mediobasal hypothalamic region (MBH), which is crucial for the neuroendocrine regulation of the physiological homeostasis of the whole body. We have previously shown that the hypothalamus has a programmatic role in causing systemic ageing. In this context, we investigated whether these hypothalamic NSCs (htNSCs) might be mechanistically responsible for this process.

We show that loss of htNSCs is an important cause of ageing in the whole body. This understanding aligns with our previous research showing that the hypothalamus has a programmatic role in systemic ageing. The underlying basis could be related to two functions of these cells: endocrine secretion and neurogenesis. Here we report that the modulation of ageing by htNSCs was achieved in a relatively short period, which should not have a major contribution from neurogenesis, while an endocrine function of these cells provided a neurogenesis-independent mechanism. In this context, we show that the anti-ageing effect of htNSCs is partially mediated by exosomal miRNAs secreted from these cells. Therefore, besides the classical endocrine function of the hypothalamus in secreting peptidyl hormones, htNSCs have a new type of endocrine function by secreting exosomal miRNAs.

Given this finding, we still predict that neuropeptide secretion by htNSCs, although not addressed in this work, also participates in the regulation of systemic ageing. This is partly because we previously found that GnRH is involved in the hypothalamic control of ageing and we observed here that some implanted htNSCs gave rise to GnRH-expressing cells. Thus, neuropeptide-based endocrine functions of htNSCs and their differentiated offsprings can contribute to the anti-ageing effects of these cells from other perspectives. Despite these outstanding questions, the overall findings in this work support that htNSCs are essential for the control of ageing speed.

Comments

It's worth noting that the survival curve for the treated group in this paper simply moved right, with a concomitant increase in maximum lifespan. This seems quite different than the "rectangularizarion" of the survival curve that seems to be more typical of drugs like rapamycin. Still, small study in mice, so can't draw too many conclusions.

Posted by: Nick at July 26th, 2017 9:10 PM

After reading a couple of recent review articles by Morris, and one by Martin, it appears that certain SNP's in the FOXO3A are active in preserving stem cell pools. This maybe one of the principle reasons for longevity if you have several alleles for FOXO3A SNP's. I happen to have 24 of the longevity alleles in 12 SNP's of FOXO3A, and hope to live to 120.

Posted by: Biotechy at July 27th, 2017 3:26 PM

This makes perfect sense and is in line with SENS and Hallmarks of aging. Stem cell depletion is one of the hallmarks of aging and does drive the aging process though not just loss in the hypothalamus of course. The good news is replacing them has been shown to reverse the issue in a number of experiements so I have less concern about loss of stem cell stocks as it will be feasible to replace them in the next decade or so once we learn how to make all the master stem cell types, and we are close to doing that now.

Posted by: Steve Hill at July 28th, 2017 6:44 AM

To preserve stem cell pools in the future you may want to have redundant protection. For example, you might use CRISPR technology to replace a block of say 10 of your FOXO3A SNP's with the longevity versions of the SNP. The longevity SNP's of the FOXO3A gene ha many, many more beneficial effects on many longevity pathways other than just stemness, so you would have protection on a broad spectrum of aging conditions.

Posted by: Biotechy at July 29th, 2017 6:37 AM

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