More on Beta-2 Microglobulin Blood Levels and Aging, Resulting From Parabiosis Research

Over the past couple of years, researchers have been involved in cataloging differences in signaling molecules in the blood when comparing old and young mice. This is an outgrowth of heterochronic parabiosis studies, in which an old and a young individual have their circulatory systems joined and the results observed. The effects are improved health, regeneration, and aspects of cell biology such as stem cell activity in the old individual, and opposing negative impacts on the young individual. This was in the news recently with a focus on TGF-β signaling and stem cell activity in the brain, but the other part of that research involves β2 microglobulin (B2M), which is front and center in the publicity materials linked below.

The orthodox theory is that stem cell activity declines with age in reaction to growing levels of tissue damage, and this happens because it reduces cancer risk, with life span emerging from the processes of natural selection as a balance between death by cancer on the one hand and death by loss of tissue maintenance and organ function on the other. The evidence to date suggests that in mammals at least this is far from a finely balanced outcome and that there is a in fact a fair amount of room to boost cell activity and regeneration in old age without greatly increasing cancer incidence.

Thus researchers are greatly interested in finding ways to restore stem cell activity in the old, and turn back loss of tissue maintenance. There is a good chance that much of this declining activity is caused, proximately at least, by changes in cell signaling over the course of aging, and especially in levels of signal molecules carried in the blood stream - which comes back to parabiosis as an investigative tool. If specific signals important in age-related decline of function can be identified, then changing their levels can form the basis for therapies.

The root cause of loss of function with age is still cell and tissue damage, however, and the best goal is to repair that damage and thus have the signaling changes revert themselves, not interfere at a higher level, even if it happens to turn out that there are benefits to be had. Even if you can improve greatly on today's medicine by restoring stem cell activity, with a backup provided by next generation targeted cancer therapies, then there is still the harm caused by forms of damage such as mitochondrial dysfunction and waste products such as cross-links and amyloid. That will still kill us if left untreated, stem cells or no stem cells.

Age-related cognitive decline tied to immune-system molecule

Connecting the circulatory system of a young mouse to that of an old mouse can reverse the declines in learning ability that typically emerge as mice age. Over the course of their long-term research on so-called young blood, however, the researchers had noted an opposite effect: blood from older animals appears to contain "pro-aging factors" that suppress neurogenesis - the sprouting of new brain cells in regions important for memory - which in turn can contribute to cognitive decline.

Beta-2 microglobulin, or B2M, levels steadily rise with age in mice, and are also higher in young mice in which the circulatory system is joined to that of an older mouse. B2M is a component of a larger molecule called MHC I (major histocompatibility complex class I), which plays a major role in the adaptive immune system. These findings were confirmed in humans, in whom B2M levels rose with age in both blood and in the cerebrospinal fluid (CSF) that bathes the brain. When B2M was administered to young mice, either via the circulatory system or directly into the brain, the mice performed poorly on tests of learning and memory compared to untreated mice, and neurogenesis was also suppressed in these mice.

These experiments were complemented by genetic manipulations in which some mice were engineered to lack a gene known as Tap1, which is crucial for the MHC I complex to make its way to the cell surface. In these mice, administration of B2M in young mice had no significant effect, either in tests of learning or in assessments of neurogenesis. The group also bred mice missing the gene for B2M itself. These mice performed better than their normal counterparts on learning tests well into old age, and their brains did not exhibit the decline in neurogenesis typically seen in aged mice.

The effects on learning observed in the B2M-administration experiments were reversible: 30 days after the B2M injections, the treated mice performed as well on tests as untreated mice, indicating that B2M-induced cognitive decline in humans could potentially be treated with targeted drugs. "From a translational perspective, we are interested in developing antibodies or small molecules to target this protein late in life. Since B2M goes up with age in blood, CSF, and also in the brain itself, this allows us multiple avenues in which to target this protein therapeutically."

β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner.

B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.


Exciting stuff once more...

As to your stance regarding repairing damage... yes, sure, except that technologically, it is a lot easier to regulate chemicals than to repair whole body damage...

And if those who are alive today want to live longer and healthier lives, we need technologically simple therapies being developed today... not hypothetical full rejuvenation that could take many, many decades to achieve...

Posted by: Daniel Lemire at July 7th, 2015 6:00 AM

Why did the Tap1 gene even evolve? Why does any living creature even produce B2M? Is this just an unlucky mutation, a defense mechanism against some long-gone disease (or an extant one), what?

Posted by: Slicer at July 7th, 2015 6:11 PM

Never mind. Should have checked the Wikipedia link. The real question is why this stuff is overproduced and what can be done about it (although targeting it with a drug seems like it'd be viable in the short term).

Posted by: Slicer at July 7th, 2015 6:46 PM

Is there any evidence for a link between lifestyle factors thought to promote longevity and reduced levels of B2M in humans?

Posted by: Lester Hiley at July 9th, 2015 10:11 PM

Inhibitiing TGF-B1 drops levels of B2M according to the conboys who have rejuvenated muscle and brain recently using this technique.

"We compared the B2M expression levels as an indicator of inflammatory response in young and old mice treated with vehicle control, and old mice treated with the Alk5 inhibitor. B2M levels were extremely low in young brain and muscle, consistent with prior work, but increased significantly with aging. Importantly, when TGF-β signaling was attenuated in vivo by the Alk5 inhibitor, B2M levels were significantly diminished both in old brain and old muscle . These results demonstrate that B2M becomes upregulated with aging in multiple tissues (suggesting an increase in inflammation) and that down-modulation of TGF-β signaling, which rejuvenates myogenesis and neurogenesis, normalizes B2M in myogenic and neurogenic regions to their young levels, suggesting attenuation of inflammation. As further support of this conclusion, the levels of B2M were also significantly reduced in regenerating regions of the old muscle administered with the dnTGFBR2, as compared to tissue administered with control GFP virus. Furthermore, addition of low concentrations of TGF-β1 (0–5 ng/mL) to immune cells, specifically BV2 cells – a microglia cell line – did not affect B2M levels, as assayed by pixel intensity and percent area staining of B2M (Supplemental Figure 6A–6C). In contrast, high TGF-β1 (50 ng/mL) levels induced a significant increase in B2M expression. Thus, physiologically young levels TGF-β1 does not induce B2M, but increased TGF-β1 does."

Posted by: Steve H at July 22nd, 2015 4:40 AM
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