Delivery of Recombinant Serum Albumin Extends Life Span in Old Mice

An interesting result is reported in today's open access preprint paper. The authors find that the life span of mice is extended by 20% or so after treatment every few weeks with serum albumin, beginning in mid-life. The researchers base their approach on noting that aging is characterized by modification of circulating serum albumin molecules, and theorize that a significant fraction of the issues arising with age are reactions to that damaged albumin. By delivering unmodified serum albumin, the damaged fraction of albumin is reduced, and the harmful reactions diminish. This is, in effect, sabotaging one of the many feedback loops in aging wherein forms of molecular damage act as signals to provoke maladaptive responses and further molecular damage.

This is most interesting when considered in the context of the beneficial effects that are reported to result from dilution of blood in old animals. Dilution studies have been carried out as a part of the ongoing debate over whether contributions to aging result from a loss of beneficial factors in circulating blood, or from the addition of harmful factors to circulating blood. That this dilution is enough to produce some degree of reversal of aspects of aging, such as chronic inflammation, argues for the harmful factor model. It is important to note that the dilution protocol involves adding albumin, as albumin is one of the few essential items present in the bloodstream that will result in major issues should it fall to lower levels. Is the added compensatory albumin the primary cause of benefits? Further studies will be needed to clarify and replicate these results.

Young and Undamaged rMSA Improves the Longevity of Mice

Here we report that a single protein recombinant mouse serum albumin (rMSA) improved the lifespan and healthspan of C57BL/6N mice. The median lifespan extensions were 17.6% for female and 20.3% for male, respectively. The grip strength of rMSA-treated female and male mice increased by 29.6% and 17.4%, respectively. Meanwhile, the percentage of successful escape increased 23.0% in rMSA-treated male mice using the Barnes Maze test. The rMSA used in this study is young and almost undamaged. We define the concept "young and undamaged" to any protein without any unnecessary modifications by four parameters: intact free thiol (if any), no advanced glycation end-product, no carbonylation, and no homocysteinylation. Here "young and undamaged" rMSA is much younger and less damaged than the endogenous serum albumin from young mice at 1.5 months of age. We predict that young and undamaged proteins altogether can further improve the longevity.

Human serum albumin (HSA) is the most abundant protein in blood plasma with a serum half-life of about 21 days. Damages or unnecessary modifications of HSA are related to many pathological conditions and increase with age. Firstly, the single free thiol in Cys-34 residue of HSA has been proposed to account for approximately 80% of the total free thiols in plasma, whose oxidation is intimately linked with aging and age-related diseases. Secondly, in oxidative environments, carbonyls are also formed especially on the side chains of residues in proteins. Elevated carbonyl levels in HSA have been found to be related to aging and varieties of diseases. Thirdly, the AGE accumulation of HSA is another important factor found to be involved in aging. It is widely reported that AGE formation impairs normal functions of albumin and can induce inflammatory responses, which is connected with aging and the progression of serious diseases. Fourthly, it has been widely reported that homocysteine (Hcy) increases with age and is associated with age-related degenerative disorders. HSA is a major target for homocysteinylation, thus it can efficiently protect other proteins from the toxicity of Hcy.

Therefore, treatment of freshly prepared recombinant serum albumin with no damages or unnecessary modifications is most likely to extend lifespan and healthspan. Here we report that young and undamaged recombinant mouse serum albumin (rMSA)-treated groups in natural aging mouse model obtained significantly extended lifespan with increased skeletal muscle strength and cognitive ability compared with saline-treated groups.

Comments

High levels of albumin indicate a good prognosis in many cancers. I wonder if there's a connection.

Posted by: Barbara T. at April 6th, 2021 5:44 PM

I wonder what other young proteins could be introduced to an aging human that would help? Could we possibly manufacture them?

Posted by: paul at April 6th, 2021 7:02 PM

Off topic: Its unbelievable to me that person who get blood cloth or stroke in brain today aren't receiving any neuroprotectants at ICU. Even carnosine, ginkgo biloba, blueberries, vinpocetine, vit K2 and other simple, cheap supplements can make a difference. I always have those around me.

Posted by: thomas.a at April 7th, 2021 12:58 AM

Unfortunately, no impact on maximum lifespan.

Posted by: Adrian Cull at April 7th, 2021 1:15 AM

The Conboys are hitting the wall around about... now.

Posted by: Tony at April 7th, 2021 4:04 AM

@paul
If proven to work there could be out of body cultured bone marrow to produce most of the blood content. If mass produced might be quite cheap, even with personalisation...

Posted by: Cuberat at April 7th, 2021 6:18 AM

This therapy is interesting and will soon be practical because Recombinant Serum Albumin can now be produced by a variety of genetically modified microbial species.

A next step in animal experiments might be to just add albumin without taking any plasma out to see if there are any health benefits. Albumin is part of the Levine phenoage calculation so it obviously has some reasonable sized effect.

Posted by: Lee at April 7th, 2021 8:15 AM

Interesting. So is dilution not enough? We have been performing plasma blood donations for decades and one would think we would notice longevity effects from if dilution was enough.

Would be simple enough for plasma donations to add back some albumin instead of just saline (like they do now) and would get many more people to donate plasma if there were some health benefits to doing so!

Posted by: Gene at April 8th, 2021 11:04 AM

Hey there! Just a 2 cents.

Yes, there is a connection, albumin is gsh/cysteine thiol rich and is one of the first line of defense in the body for ROS detoxification. Studies showed that plasma was correlated with protection, so long as albumin fraction was there and was gsh heavy. Plus, I would wager gssg/oxidized cysteine poor because the ratio of gsh:gssg or cysteine:ox.cysteine in albumin is causal to plasma/blood redox shift. When the gsh:gssg high ratio-blood enters area with more ROS, soon enough ROS will lower as gsh will be consumed (from albumin) to quench them. I am only talking of Excess emission ROS (oxidative milieu balance tipping (antiox vs ox; redox shifting to ox over antiox), not standard/basal ROS (signaletic).

But, there is a twist (like always), a bad one, which is that redox is highjacked by cancerous cells; meaning ROS levels are higher in cancer cells but not so high as to kill cells; it is continuous 'low-grade inflammation' to create 'rogueness/become cancerous', thus it requires a higher ROS level; but cancer cells use gsh, they form more gssg; but are gsh depleting; because they are 'boosting inflammation' so they counter it by depleting your precious gsh; and create gssg (by oxidizing milieu - just enough, to maintain 'cancerous' state - forever when they divide infinitely); studies that would see improvement from albumin in cancerous patient is because ROS is being Further quenched or inflammation-DNA damage is being substantlly reduced (because cancer cells cause inflammation/SASP; and SAPS may cause HSAF, Heterochromatic Senescence Associated Foci; or chromosomal damage/telomeric foci (y-H2Ax)). This can lead to oncogene activation (senescence; Senescence as compensatory mechanism - to kill cancer cells/to stop them from turning cancerous; p16-p53 tumor suppressor genes that suppress cancer by Boosting ROS; Fight Fire with Fire - destroy cancer - and kill you, in the process because so strong that even peripherical healthy cells sustain damage of cancer destruction process, it's not perfect nor 100% precise (remove bad weed/unfunctioning/compromised from specie, no matter to natural selection, selected for elimination because compromised/compromising specie survival if transfer of unselected genes (reproduction during compromised event)). Fire burns other (and you), even you(rself) if you play with it/or use it to destroy other. It's a balance clearly, it is only meant to be use sporadically and well-controlled, not uncontrolled and 'let loose' because then you will 'burn yourself' while doing it (a bit like when parents told you : ''don't play with matches''; they were onto something).

Gsh poor albumin, bad, redox shift towards oxidized milieu, it will increase in +mV (a (less) Reduced milieu) and as such there will be low-grade inflammation/oxidation and this contributes to cancer progression.

Yes, no impact on maximum lifespan...redox is important to reach maximum lifespan; toads injected with gsh in brain, have 50% extension of lifespan and maximum; that is because gsh thiols control redox and redox is important to keep it a lowest grade inflammation/lowest damage from this inflammation. Same with quahos/bivalves, they have maintenance of redox (and they live 500 years). Same for people doing yoga, they have gsh boost after a yoga session, and that is a large reason why yoga is benefitial on lifespan/health; otherwise, it would do jack. Well, if you believe in it, it could do something (placebo), your mind is strong and itself it could very well boost your gsh, from Believing whatever (even fake/false stuff) (the saying is Seeing is Believing, or Believing .. is Believing, or something like that). Placebo effect strongest and 'works in tandem' with body/mind/resilience/survival. Of course, placebo may do almost nothing also. But that is not the total story, the real Story, is epigenetic drifting and epigenetic clockl that is the biigger determinant of maximum lifespan. So long as there is suffcient mitotic clock availability (in other words, no short telomeres).

The discrepancy between epigenetic clock and chronological time determines maximum and average lifespan in all animals. The further the former is, the further animal is close to death. The larger the discrepancy is the former is to latter, the more it is either closer or farther to death. If the former is behind the latter, then maximum will increase; the latter is inconsequential (over the former). The latter is only a measure of time passed (in years). One could have a very advanced former and much less advanced latter; that means rapid death (younger person dying rapidly, not of damage, but epigenetic acceleration such as progeria HGPS/Werner/T21 causing epigenetic acceleration). Animals that live centuries maintain a minuscule former and an extreme latter. Thus, the discrepancy is largest in them (LATTER vs former); in inverse, of people who also have largest discrepancy, but die very young/prematurely (FORMER vs latter). Thus, the larger the discrepancy between the 2, the Longest or Shortest is avg/max lifespan. (There is no 'chronological clock' per se, it is only the 'time' that passed, in real-time years. The person's age in other words. Thus, Chronological Time passed to this day/living in life (in years)).

The only way I see increase of animals above MLSP will be when we are able to alter clock to Increase Discrepancy, the good one/right one, which is epigenetic clock (biological age) holding steady/frozen and chronological time passing/increasing; increasing the discrepancy/gap between them. Not, obviously, increase the Inversed discrepancy (i.e. epigenetic drifting causing epigenetic clock advancing further/much further...than chronological time passing; in other words biological age is much more 'aged/advanced' than the actual chronological time passed; that means being 'biologically older' - that how many years your lived; that is being closed to biological death (per epiclock)).

Just a 2 cents.

Posted by: CANanonymity at April 9th, 2021 3:43 PM

To me, this could be a real breakthrough and offer the first practical anti-ageing treatment for humans if the manufacturability of recombinant albumin and others blood proteins is scalable (I have no expertise at all in this domain).

There was no detected impact of maximal lifespan but could it be due to the small number of animals (50 in each group)? In any case, a new experiment with more animals and two control groups (one with no treatment and one with saline injections) would be useful to confirm the results.

Still, the wide range of observed benefits (increased skeletal muscle strength, cognitive ability, decrease level of phosphorylated-tau) suggests a robust impact.

I would not be surprised to see a startup in the next year or so jumping into that area.

Posted by: Interested reader at April 10th, 2021 11:29 AM

"Mice were injected with 1.5 mg rMSA per gram of mouse body weight and isometric saline every 3 weeks as indicated."

If those numbers scale up that would mean about 100 grams would be needed for a 70kg human. A quick search shows 100g of pure human albumin costs around $25,000 US for just one dose/treatment, and many doses are required, though bovine serum albumin is only ~$250 for 100g.

I know it's a bit early to be talking about self experimentation, but I wonder if bovine serum would work as an alternative? If not, is there any way around the current (6-figure?) cost of human albumin serum?

Posted by: Kel at April 12th, 2021 7:31 PM

@Kel

The high costs are due to the very niche usage. If the results can be reproduced for humans there will be a huge incentive to do the R&D and mass produce it at reduced cost. There's a possibility to culture the cells that produce it, use transgenic animals to make it human compatible and such. But it is very likely that it's not the albumin itself they is needed but only a small compound. Even more important would be to remove the compromised albumin than doing a simple dilution. This might turn orders of magnitude more effective.

Posted by: Cuberat at April 12th, 2021 9:05 PM

@Cuberat

Thanks for the response. I hope you're correct. Unfortunately, all that will take time, so dilution may be the only option for a while.

As an aside, it's interesting to note that it was also albumin protein leaking past the blood brain barrier that caused dementia, which was then reversed with a drug, in a study Reason posted about a little over a year ago: https://www.fightaging.org/archives/2019/12/blood-brain-barrier-dysfunction-causes-chronic-inflammation-and-neurodegeneration/#comments

Posted by: Kel at April 13th, 2021 2:40 PM

@Kel
Now we are at the point where we need any treatment proven to work in humans, regardless of the financial costs of the treatment. And by working I mean actually reversing age-related conditions and not busy giving barely statistically significant improvements like fisetin.

The moment we have a proven treatment the money for R&D will be poured both from the governments and commercial investors.

Posted by: Cuberat at April 13th, 2021 6:33 PM

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