Aging Can Spread Through Your Body Via a Single Protein, Study Finds 18
alternative_right shares a report from Phys.org: Take note of the name: ReHMGB1. A new study pinpoints this protein as being able to spread the wear and tear that comes with time as it quietly travels through the bloodstream. This adds significantly to our understanding of aging. The researchers were able to identify ReHMGB1 as a critical messenger passing on the senescence signal by analyzing different types of human cells grown in the lab and conducting a variety of tests on mice. When ReHMGB1 transmission was blocked in mice with muscle injuries, muscle regeneration happened more quickly, while the animals showed improved physical performance, fewer signs of cellular aging, and reduced systemic inflammation. The findings have been published in the journal Metabolism.
Why is it floating around (Score:5, Interesting)
So what's it doing outside of the nucleus? Is it supposed to do that or is it some consequence? A study I found says that these proteins are released when a cell goes through apoptosis or other forms of cell death. Also appears to be released during netosis, which is thought to be an offensive death measure taken by neutrophils to break down fungus or other larger than digestible pathogens. If other cells see it and it triggers senescence, maybe its a signal that the body is under stress from some sort of pathogen, as HMGB1 isn't supposed to be out of the cell, and if it is, its a sign of infection, senescence being a protection mechanism to prevent too much cell death (how about that for a run on sentence).
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Stress, a risk factor for major depressive disorder and Alzheimer disease, leads to the release of high-mobility group box-1 (HMGB1) protein, which in turn causes neuroinflammation. The mechanism underlying stress-induced HMGB1 release is unknown, but stress-associated glucocorticoids could be involved. Primary cultured rat cortical microglia and neurons were treated with corticosterone, a stress-associated glucocorticoid, and HMGB1 release was measured by ELISA and western blotting to test this hypothesis. With corticosterone treatment, significant HMGB1 was released in microglia but not in neuronal cell cultures. HMGB1 mRNA expression and HMGB1 protein expression in microglia were not affected by corticosterone treatment. Thus, the source of extracellular HMGB1 released into the medium is likely to be existing nuclear HMGB1 rather than newly synthesized HMGB1. Corticosterone-induced HMGB1 release in microglia culture was significantly attenuated by blocking glucocorticoid receptors but not mineralocorticoid receptors. Dexamethasone, a selective glucocorticoid receptor agonist, and dexamethasone-bovine serum albumin (BSA), a membrane-impermeable glucocorticoid receptor agonist used to confirm the membrane receptor-mediated effects of glucocorticoids, increased the release of HMGB1. Immunocytochemistry showed that HMGB1 translocated from the nucleus to the cytoplasm following dexamethasone or dexamethasone-BSA treatment through glucocorticoid receptors. The present findings suggest that glucocorticoids stimulate microglial membrane glucocorticoid receptors and trigger cytoplasmic translocation and extracellular release of nuclear HMGB1. Thus, under stress conditions, glucocorticoids induce microglial HMGB1 release, leading to a neuroinflammatory state that could mediate neurological disorders. https://pubmed.ncbi.nlm.nih.go... [nih.gov]
Glucocortisoids act like a epigenetic reset button?
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I suppose this makes some sort of evolutionary sense. Older creatures living in high stress environments age and die more quickly, releasing resources for younger ones still in their most reproductive years. Wonder if this is mammal-specific, or across the animal kingdom.
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Cancer expresses HMGB1 too, the inflammation is probably an anti-cancer mechanism.
looks like I was wrong (Score:2)
as soon as HmgB1 goes outside the nucleus, it acquires completely different functions, post-translational modifications, and change of its redox state.
High-mobility group box 1 protein (HMGB1) serves as an inflammatory mediator and has been implicated in the pathogenesis of asthma. Extracellular HMGB1 transduces cellular signals through the plasma membrane receptor for advanced glycation end products (RAGE). The HMGB1/RAGE axis has proven to be a pivotal factor in the progression of tumor growth and inflammation. In this study, we sought to determine whether HMGB1 signaling through RAGE occurs in asthma. Conclusion: In conclusion, a part of the HMGB1 contribution to the pathogenesis of asthma was mediated through binding to RAGE.
NETs overproduction promoted glioma cell proliferation, migration, and invasion. Furthermore, HMGB1 was found to bind to RAGE and activate the NF-B signaling pathway in vitro.
Green tea extract to the rescue
experimental evidences indicate that EGCG can induce the aggregation of HMGB1 protein, a late mediator of inflammation, which subsequently stimulates the autophagic degradation and thus provides protection from lethal endotoxemia and sepsis.
Some interesting info.
HMGB1 is an important player in nuclear transactions because it is very abundant (about 1,000,000 molecules) in most mammalian cells, is extremely conserved between species, and Hmgb1 KO mice are not viable. https://www.cell.com/action/sh... [cell.com]
With 1 million of these HMGB1 per cell, dumping them into the extracellular plasma might cause quite a reaction (binding to RAGE and precipitating neutrophil extracellular traps). Looks like it might be to fight biofilms.
The extracellular innate-immune effector HMGB1 limits pathogenic bacterial biofilm proliferation https://www.jci.org/articles/v... [jci.org]
Might be linked to other diseases too, like alzheimers?
RAGE activation induces AB production https://pmc.ncbi.nlm.nih.gov/a... [nih.gov]
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Yeah, although from an evolutionary perspective, the sooner you die once your kids can survive alone the better it is. Like kids move out and next day you can die
Repeat for kids generation. That ensures more generations can fit into a given time and thus faster evolution.
Like 500 year life span turtles and 3000 year old trees vs insects with few day life span or bacteria & viruses / virii evolving on timescales of weeks.
That's the only way to Sapiens 2.0 - which will definitely look like Avataar. or Mat
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200 year lifespan for tortoises is probably a different result of adapting to scarce resources, rabbits on islands tend to quickly wipe themselves out by over reproduction resulting in starvation.
I suppose there are two paths to long term success for a species, limit your numbers to the carrying capacity of the environment or expansion into new territories. If you can expand to new territories and there are sufficient resources there then stress would be reduced and the critter lives longer with more chanc
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And this evolutionary perspective works to advance the species only if:
0) Your offspring need only as much information, training, and experience as you can give them in your short lifespan, or...
1) We invent language, writing, and the printing press to convey knowledge to the succeeding generations.
'Faster evolution' in your scenario might be genetic evolution, which is perfectly cool, but pales in comparison to the effects of all else. Waiting for genetics to solve what problem we cannot solve with technol
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It's helpful in the short term but causes problems if it is constant, chronic stress.
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Breaking the cells via injury, disease, or (in this case) senescence allows HMGB1 to spread causing a cascading inflammation response
In many ways, an inflammation response is useful such as reducing blood loss or reacting to an infection
However, inflammation, over the long run, causes many conditions that can reduce lifespan
I skimmed the paper in Metabolism and did a search on how to reduce intra-cellular HMBG1 release and got to this point: Metformin can inhibit nuclear HMGB1 translocation to the cytosol,
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Yes, that is a summary of the first two lines I wrote
I think that beyond that, people would be interested in how to stop that, and my searches indicate that Metformin (which has been used effective in other life extension research with roundworms and mice) accomplishes that
I am on Metformin, and encourage others to do the same
dammit (Score:2)
Billionaires that arw getting blood transfusions from younger people might actually be working.
Inhibitor (Score:3)
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purified anti-HMGB1 antibody 3E8 clone mAb (Bio-Legend, San Diego, CA, USA; 651402) by intravenous injection (i.v., 0.1 mg/kg) [24]. After 24 h, 50 uL of 1.2 % barium chloride (BaCl2) (Sigma-Aldrich; 202738) solution dissolved in saline
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...in mice (Score:2)
So we'll soon be able to make mice live longer. Humans though, that's an other story.
There are so many studies done on mice with promising but yet not reproducible results when done on humans.
Especially studies on ageing since mice age much faster than humans.
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There are so many studies done on mice with promising but yet not reproducible results when done on humans.
And there are many studies done on mice that bear fruit. When a new wonder drug is approved for humans the mice don't event get a mention. [wikipedia.org]