Further Investigation of the Role of Osteopontin in Hematopoietic Stem Cell Aging
The Hematopoietic stem cell population resident in bone marrow is responsible for generating blood cells and immune cells. Like all stem cell populations, their activity alters and declines with aging. This is one of the causes of the progressive disarray of the immune system in older individuals. If we want to rejuvenate the immune system, then restoring the youthful activity of hematopoietic stem cells is one of the items on the to-do list, alongside regrowth of the thymus, and clearing out the accumulation of exhausted, senescent, and misconfigured immune cells.
The protein osteopontin appears to have a sizable role in maintaining the hematopoietic stem cell population, but levels fall in older individuals. Researchers have demonstrated, in mice, that restoring high levels osteopontin can also restore a significant degree of hematopoietic stem cell activity. This is promising because it is comparatively simple to achieve and package as a therapy, but equally it isn't addressing whatever root causes underlie this narrow view of the picture. The open access paper here continues the investigation of osteopontin in the context of hematopoietic aging in mice, adding further evidence for its relevance.
In mammalian tissues that undergo high cell turnover, such as the hematopoietic system, a small population of stem cells maintains organ regeneration throughout the animal's life span. However, the functionality of stem cells declines during aging and can contribute to aging-associated impairments in tissue regeneration. Accumulating evidence indicates that aged hematopoietic stem cells (HSCs) increase in number due to a higher rate of self-renewal cell divisions while displaying reduced ability to reconstitute the immune system.
The phosphorylated glycoprotein osteopontin (OPN) is an extracellular matrix component of the bone marrow with important roles in tissue homeostasis, inflammatory responses, and tumor metastasis. The expression of OPN within the bone marrow is highly restricted to the endosteal surface, a location where HSCs have been found to reside preferentially. OPN binds to cells through integrins or the CD44 receptor, subsequently activating multiple signaling pathways. When HSCs are transplanted into wild-type (WT) or OPN knockout mice, they exhibit aberrant attachment and engraftment, suggesting the dependence of HSCs on OPN in these processes. Moreover, OPN deficiency within the bone marrow microenvironment results in an increase in primitive HSC numbers. More recently it has been reported that osteopontin exposure to aged HSC can attenuate their aging-associated phenotype.
Here, we study the impact of OPN on HSC function during aging using an OPN-knockout mouse model. We show that during aging OPN deficiency is associated with an increase in lymphocytes and a decline in erythrocytes in peripheral blood. In a bone marrow transplantation setting, aged OPN-deficient stem cells show reduced ability to reconstitute the immune system likely due to insufficient differentiation of HSCs into more mature cells. In serial bone marrow transplantation, aged OPN knockout bone marrow cells fail to adequately reconstitute red blood cells and platelets, resulting in severe anemia and thrombocytopenia as well as premature deaths of recipient mice. Thus, OPN has different effects on HSCs in aged and young animals and is particularly important to maintain stem cell function in aging mice.
Are there any known substances that can upregulate SPP1's encoding of osteopontin? The article mentions that the levels decline with increasing lymphocytes, is there anything that can be done to reduce those? Why do lymphocytes increase?
Perhaps much of this OPN deficiency and associated conditions simply have to do with the Use it of Lose it principle. Most elderly people have declining use of their large leg bones and muscles during aging. A study should check to see what greatly increased daily activity in the use of the large leg bones and muscles would do for the deficiency parameters mentioned in the article.
Hi there ! Just a 2 cent.
''If we want to rejuvenate the immune system, then restoring the youthful activity of hematopoietic stem cells is one of the items on the to-do list, alongside regrowth of the thymus, and clearing out the accumulation of exhausted, senescent, and misconfigured immune cells. ''
This will definitely help for sure with hematopoietic stem cells. Thymus regrowth too, this is one major point of the immune system; currently, the best way to hinder thymus involution is to boost immune system; such as darkness therapy or immune activating therapeutic herbs (echinacea and such). It's why I am a bit concerned about WILT (whole body interdicting telomere lenghtning) in cancer cells. But, all in all, it should be ok as long as there is no an immune weakening effect by WILT; since it will deprive telomerase to immune cells, or stem cells using it. And the studies previously showed it was more important to boost immune power than 'prevent cancer'; because the latter was much harder to do than the former; the former would use the immune's system reinvigorated power to kill cancel cells (via macrophages, T/NK cells detecting them and phaging them...); the studies said a More Powerful and 'young' immune system is a Wiser move than trying to abate cancer with other tricks; for you Need the immune system to eradicate these cancer cells (p53/TNF-a genes can only do so much through ROS production to destroy cancer cells; it must be a 'concerted (immune) effort' to kill cancer cells).
I think a better solution than immune system or even WILT, is epigenetics.
This brings me to my next point,
I am not at loss about the whole 'ol' debate (which should't be one since we have both) of whether it's damages or programmed.
Now, I'm axing (back) towards more programmed aging (like I was long ago and, in fact, was righter then). I have come to understand (recently through another eureka moment),
that damages are stochastic process of another stochastic process : epigenetics, I don't mean just genetics; but Epigenetics.
That DNA methylation clock (epigenetic clock) is FAR more causal to aging than we thought. We thought all along it's all damages or just genetics; when (I feel) it's more epigenetics the bigger culprit. Thus, programmed (aging).
How I made this up is that I foudn out that, apparently, when iPSCs are reprogrammed they have increased télomères and they back to youth phenotype. Now the telomeres part is quite 'flexible'; and telomeres are important but in fact can be completely ignored for reprogramming. The study demonstrated that cells that enter senescence have dramatic changes in epigenetics. And that these epigenetics changes happened Before, During and After senescence (such as replicarive senesnce); they are a continuous 'thing in the background' - that Supercedes the senescence process. That's because they are the epigenome which is the guardian of chromosome stability - I thought it was telomeres apparently not; telomeres are Mostly a counter and a signaller; the more important one is the DNA methyl clock/epigenetic clock. It's role is to control gene silencing and activation; through methylation in CpG-rich/poor islands.
The stydy showed that senescent cells accumulated HSAF 'heterochromatin senescence-associated foci', this demonstrated that chromosomes and epigenome were Behind the senescence process; and when these cells were retroprogrammed towards undifferentiated 'fetal/stem-cell' like state it took one week for the HASF to dissapear; and it did disappear as if it never appeared in the first place. It was Reversal of Aging, by Disappearing of 'damage HSAF' to chromosome.
And this is important : cells that had increased telomeres (via ALT/telomerase hTERT) - did not stop senescence-state, after culturing them for 5 or PDs the cells entered growth arrest and senesced - Despite Newly Increased TElomeres.
This demonstrated certain things :
- Telomerase/telomeres elongation, sadly, cannot thwarth aging process because of epigenetics.
- Damages are controlled by epigenetics; damages contribute in a stocastic change in epigenetics in a futile 'stocastic' downward spiral of the epigenome trying to 'bounce back' but can't. Damages are the consequence of imperfect genes, imperfect processes, imperfect repair, and so forth; epigenome can only do so much until it acn't bounce back anymore and its 'state' is changed (which contributes to 'Aging' as we know it).
- Epigenetics determine how aging, more than damages or anything else combined, because they regulate the genes and many repair/protecting/syntesis mecanims required for genome functionning.
- I am not sure, now knowing this, that LEV is possible (anymore) because damage repair does not reverse epigenetics. Epigenetics are controlled via a 'memory' mechanism, cells have 'memory' and 'remember' 'how old' they are; it's why they 'know' when it is soon senescence, and that'S not just telomeres deciding this; telomeres can be Independent from this; they are cell cycling counters; but the DNA methyl clock Supercedes telomeres.
- This 'memory' mechanism is reponsible for why reprogramming is the Only way to Reverse aging, while damage repair Slows it but does not STop it neither Reverse it. The epigenetic signature Supercedes all damages and whatnot, this memory 'Signature' is what makes a human 'of such age'; it is an Irreversible state - not through damage repair is it possible; only through cell reprogramming; as seen in iPSCs reprogramming that completely remove damages, enhance telomeres and make them have a 'new signature' that of a (youth-like/'age 0') undifferentiated cell/like a stem-cell or cancel-cell. You cannot simply say 'Repaire damages' and you get LEV, impossible because of this memory/epigenetics problems; these are irreversible (up to a certain point whence 'went too far' in time) changes on the DNA decorum; reprogramming is capable of completely twarth this; As for 'extra-cellular' damages that's another problem; they should technically resolved themselves but most likely not because they are permanent/irreversible too; Thus it means this :
aging could be Reversed via epigenetic reprogramming but it would not be 'reversed' per say; only 'frozen'; when you maintain your current 'damage level' but you are 'frozen' there; thus not 'aging' anymore (not acquiring an 'older' epigenetic signature phenoptype). Who cares if you are '30 years old forever'...it might sound like 'Groudn Hog day' forever (like Bill Murray waking up the next day - forever the same age and living the same day, forever)...but, at least, death does not come because mortality is now 'frozen', because 'aging' is frozen.. just like Naked Mole Rats that 1 out of 10,000 chance of mortality at 30 yeas old. Essentially, their mortality levels do not rise with age and they are 'technically' 0% mortality; thus 'don't die'. This is possible, and would be amounting to LEV, but repairing damages sadly, from the epigenetics infos so far, do not show that LEV is possible if you concentrate just on damages because these 'memory limits/signature' are imposed on the cell epigenome as you age. You cannot evade it, it's a 'Coded' signal/signature. Only reprogramming can. IT's why now I believe that aging is programming;
but more precisely - Epiprogramming. SENSE should put more apples in their epibasket and add new reprogramming thérapies.
Just a 2 cent.
No sens repair doesnt address epigenetic alterations but hallmarks does. Salk and church are both working on resetting epigenetics. Agex is also doing some like this via telomerase and their iTR tech based on xell reprogramming.epigenetic changes can be repaired just like any other damage assuming you consider it a reason we age and not consequence. We are likely to know either way as i said before.
Also you are confusing programmed aging theory with epigenetic programs cells are regulated by. This isnt the same thing and is muddying the water.
And for clarity here. When i say sens does not address it i mean not directly as a damage type like the 7.
Hi Steve ! Thanks for that.
I guess they kind of interlap though. Programmed aging theory is stipulating that there is programmed 'program' going on at play; from birth mostly and it controls the aging process. There is a kernel Truth there, but it's not the entire portrait. The epigenetics, which is mostly environment/external-causing', are the other element missing in that portrait. It is more muddied than we think with more shades of brown inbetween. Epigenetics are a process since birth too, and are the 'memory events' if you will; that lead to your signature chanfing over time. It's a 'state' and changes as time passes and you expose it to environments/external effects; thus it is a programm too. Maybe not in the same way as programmed aging; but it works the same way; through the programmed 'programm' (in this case the DNA decorum/methyl clock/chromsome changes/histone changes that alter the genetic/genome functionning because it acquired a new 'state'/signature).
Yes, exactly, epigenetics can be reverted; I'm only saying they must be; if not Lev is not possible without them done. The only way is reprogramming via the OSKM factors (such as OCT NANOG SOX, etc...). These stem cell factors are capable of reverting the epigenetic state; I'm not sure how the other scientists do it to revert epigenetics; I'm just basing myself from iPSCs reprogramming studies.
SENS should add an 8th therapy, that one. Otherwise, 7 therapies is not enough to make LEV, we will need reprogramming in other therapy.
What scares me though, is when you make reprogramming it's when you start playing in deep stuff, and we don't know yet the effect of Whole Body reprogramming in large mammals. It'S also kind of scary knowing reprogramming 'erases' everything and once it's done, it's done; thus, errors should be kept minimal (just like 'erasing' something by error) or else you may die in the process or not 'be' anymore (yourself/former self).
Just a 2 cent.
The Latino population in the United States lives 4 years longer on average than the other Caucasians in our country. Epigenetics studies show that they also have an epigenetic clock that confirms this, so we should try to figure out what epigenetic factors are conferring this longevity factor to Latinos.
There are important clues to be realized in both the ability of non-human organisms (the regenerators - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706275/), as well as similar proxies in humans (during active embryogenesis - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC433040/) to make a future visison of (as you say) "whole Body reprogramming" more translatable
We must keep in mind that "reprogramming" denotes a bi-directional process, either going back to pluripotent state 'A' and then induced forward, in a controlled manner, into a new set of lineages (in the case of embryonic or epimorphorphic or symplasmic generative dynamics) or, in the case of morphylaxis, a sideways trans-differentiation dynamic between terminal lineages
Pure "de-differentiation" refers to a state of pluripotency that is a uni-directional dynamic from a differentiated terminal state 'G' or 'K' or 'S', back to a starting state 'A' - what OKSM is ~"ok" at doing, but which is far from where we need to get
While they both acheived the Nobel, Yamanka peeled off / reduced a small set of the "Gurdon knowledge base" for his iPS strategy - https://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/press.html
Translational whole body reprogramming will require much more than OKSM factors, as this path alone would either 1) if accomplished in modest "salt-and-pepper" expression patterns, would likely be diluted out by your body's cell competiton dynamics (http://jcb.rupress.org/content/200/6/689.full) or 2) if accomplished at "teratoma critical mass", without proper re-differentiation guidance, turn you into a giant tumor
We still have much more to learn, especially as in concerns "teaching" an adult tissue micro-environment how to accomplish controlled, developmental morphogenic activity
Part of it will no doubt be biochemical, but many other tools, like those being developed at Tufts by the Levin lab (http://ase.tufts.edu/biology/labs/levin/) will need to be incorporated into a complete model.
But I think we will get there
@CANanonymity Yes Programmed aging and damage certainly overlap. There is no doubt some element of program involved in aging, and epigenetic changes, telomeres, and DNA expression changes are part of that. But damage also plays a role too. As I have said numerous times in the past, it is not one or the other, it's most likely both.
The work of SALK is very much supporting this idea that epigenetics is a reason we age not a consequence.
@Ira S. Pastor
Hi Ira ! Thank you very much for this very detailed explanation !
Hi Biotechy ! Thanks for that, I wonder too; it might be Something to do with telomeres at birth (such as obtaining taller telomeres, from birth; just like centenarian offspring). IT could also mean better methylome/global DNA methyl profile preservation (again, like centenarian offsprings show vs offspring of non-long living regular-life parents; they show delayed DNA demethylation).
Hi CANanonymity ! Thanks for your various comments above on possible Latino longevity factors. I know that Blacks who live past 85 are likely to live quite a bit longer than other races and that most have ancestry from West Africa where FOXO3A longevity frequency SNP's are much higher than anywhere else in the World. I speculate this may have something to do with the longevity of the long-lived Blacks. Now maybe the Latinos have a FOXO SNP complex in their genome that allows longer life as well. Another longevity related thing is that women live about 5 years longer than men. Could it be that FOXO4, which is found on the X chromosome near the centromere could confer extra longevity to females because they have 2 copies of the FOXO4 gene, while men have only one copy because men only inherit one X chromosome? Just some thoughts I had on that longevity subject.
@ CANAanonymity, you said 'cells that had increased telomeres (via ALT/telomerase hTERT) - did not stop senescence-state, after culturing them for 5 or PDs the cells entered growth arrest and senesced - Despite Newly Increased TElomeres'.
What study showed this? In the Horvath paper I read, telomerase immortalized human somatic cells continued to divide without end even though methylation as measured by the Horvath clock continued to advance.
Hi Mark !
''Because we have shown that the mean telomere length is essentially the same in both cycling (young) and noncycling (senescent) fractions of cells separated from the same culture, we cannot rule out uncapping of a single telomere as a mechanism that results in division cessation.''.
''The growth arrest that occurred after 20 PDs had some characteristics of cellular senescence but is not due to telomere shortening as shown by telomere ...''
This means it is not so much telomere length the problem as to telomere structure stability/methylation and 'capping' (shelterin complex); if telomere is uncapped whether tall or small, it is unstable and equals senescence entry/DDR signal. In regular aging, it is more 'replicative senescence' (where there Is telomere loss over time (about 50 TTAGGG bp/year); while 'spontaneous senescence' is what they are talking about when you see cell growth arrest with no telomere change (it's 'spontaneous' (inflammation caused) and works the same pathway, using p53/p16...but, it is telomere-independent; while 'replicative senescence' is the 'aging' one, that happens over time passing it is a limit by the cell cycling counting mechanism of telomeres shrinking with time.
I'm having all the difficulties finding that darn paper I had found that spoke of that; it's the most important one and I made an error to not save the PDF, just open it/read it (to not accumulate a pile of PDF like I did in the past); now I'm having all trouble finding it again; I searched on Google to no avail and looked at my browser history; but internet explorer history is not clear so I can't find it after hours seeking it again using the key words I remember; I apologize, I will try to find it (I did read this : ), it said 'cells senescend after 5 PDs/entered growth arrest' and they had now tall telomeres because were reprogrammed or had telomerase boost; so it made no sense but it showed that even if they did have tall telomeres they stopped dividing; it is possible that this is due to spontaneous senescence rather than replicative senescence.
Although certain other studies where the cells are cultured to 'replicative senescence' also show Both telomere loss And No telomere loss, so it's confusing. I think it's that thin blurry line between 'spontaneous senescence' vs 'replicative senescence', they overlap each other but are slightly different pathways. Plus depending on the epigenetic signals a senescence could mean either a 'replicative one' or a 'spontaneous one'; it's why there are confounding/contradicting results with telomeres; it depends on the 'state' of the cell and its epigenetic signature.
Here are few other ones :
Early-Senescing Human Skin Fibroblasts Do Not Demonstrate Accelerated Telomere Shortening
Telomere Cap Components Influence the Rate of Senescence in telomerase-deficient yeast cells
Five dysfunctional telomeres predict onset of senescence in human cells
Telomere-independent cellular senescence in human fetal cardiomyocytes
Here's another one that throws a monkey wrench in the figurative cogwheel process. Albeit it is in nematode cells, not mammal cells plus we live orders of magnitude longer than a nematode worm; but, still it shows that telomeres are all about 'state-dependent' and even short telomeres can be viable (if capped correctly); as what happens with cancers thriving with 2 kb small telomeres. Longer-lived C.Elegans had Either Long or Short Telomeres, made not much difference.
Uncoupling of Longevity and Telomere Length in C. elegans
''Collectively, our data indicate that telomere length and life span can be uncoupled in a post-mitotic setting, suggesting separate pathways for replication-dependent and -independent aging.''
This translates as :
''...separate pathways for replication-dependent (Replicative senescence/Telomere-Dependent)
and -independent aging (Spontaneous senescence/Telomere-Independent).''
'' Another longevity related thing is that women live about 5 years longer than men. Could it be that FOXO4, which is found on the X chromosome near the centromere could confer extra longevity to females because they have 2 copies of the FOXO4 gene, while men have only one copy because men only inherit one X chromosome?''
Absolutely,. This has been demonstrated, that the longevity of women is due to double-XX, men make do with Xy. As you specified this makes for more FOXO for having more copies. Not only that, they are smaller and fit with the IGF/FOXO/SIR axis theory; they are small, less muscle, less mTOR (mTOR/IGF (Insulin Growth Factor) is for growth/fitness/muscle at the cost of cell replicative life loss), more FOXO/DAF/SIR, more Histone Methylation of FOXOs which activate Phase II detox enyzmes, HSFs/HSPs/UCPs and NRF-2 in nucleus of Redox, thus it is at the chromosome level and epigenetics are behind it too (For it control FOXO through chromosomal (re)arragnement in methylome/histone H3 Histone H3, they are implicate in the chromatin, and FOXO/DAF/SIR/IGF/mTOR is Downstream of this; same thing for SNPs playing, like epigenetics, in this). Plus, because they have higher estrogen levels, they have higher telomerase levels than males; thus are confered more replicative lifespan in certain cells that do use telomerase (for post-mitotic cells are absent of telomerase); estrogen hormone (through IGF/GH/sexual growth hormones) activâtes estrogenic receptors and it was foudn that they directly activate telomerase (in men, it is also the same but there is an extra step with aromatase converting testosterone to estrogen, and then activatign the estrogen receptor in males; If there is such conversion it means that females are confered a 'straight' advantage by having direct access to telomerase in certain tissues; just like males have direct access to telomerase in testicules for sperm telomere elongation; unlike female ovule eggs whom are limited and don't have acces to telomerase in the level that males do to be able to continuouslty produce sexual sperm/eggs that have increased télomères (for older fathers' sperm has Longer Telomeres because of 'time'; they lived a long time and had enough time (For telomerase) to do its job of elongating the sperm telomeres (it takes years; that is why children born to older fathers generally live longer because they optain taller telomeres at birth from older father tall-sperm telomeres. Much Older fathers can give DNA defects/sperm could have oxidative lesions from their age but it seems telomerase ends up making a sperm that is more than adequate despite old age of father. Thus, it becomes a 'reward', just like grand-mother theory (old grand-ma gave their longevity genes to the generations and why we live so long, because of them - because They Lived Long and transfered that to Us through genetic/maternal mtDNA); while old fathers it is the same, the reward is 'long telomeres' to child, because father lived long; thus child reaps benefit (just like 'long-lived' grand-ma giving 'long-live genes'(akin to centenarians giving their genes to offspring; and not so surprisingly, these children have longer telomeres, less demethylation, better FOXO, protected, more redox preservation, etc...and, of course, live as long as their centenarian parent (unsurprisingly))))
Just 2 cent.
CANanonymity, I think you are getting mixed up by the different causes of senescence. Mice cells in vitro senesce quite quickly even though they have long telomeres by telomere independent mechanisms such as replicative/ROS induced stress. Human cells in vitro senesce mainly due telomere attrition. Also we know that telomerase immortalized human cells continue to accumulate the changes mapped by Horvath, but this has no detrimental affect on them. So I expect that the epigenetic alterations that are independent of telomere length probably have more to do with cell type differentiation, and probably only affect stem cells. Hence why short telomeres and epigenetic age independently influence mortality in human cohorts.
Posted by: Steve Hill at February 17th, 2018 9:17 AM: The work of SALK is very much supporting this idea that epigenetics is a reason we age not a consequence.
This study actually doesn't tell us anything at all about the role of epigenetics or epimutations in aging. Remember, somatic cells are never pluripotent, so it's not as if OSKM were here "resetting" cells to a prior youthful state that had somehow been corrupted by a lifetime of somatic epigenetic changes. Rather, Belmonte and colleagues here introduced something completely novel into aging tissues that had neverbeen there previously. Via in situ reprogramming, they were able to provide a completely novel and fundamentally unphysiologic source of stem and progenitor cells that then contributed to regenerative capacity. Whatever role one might hypothesize epigenetics and epimutations to play in aging, this is one that we can rule out.
Whether this would actually be of benefit in normally-aging mice or humansis a separate question entirely, and one that wasn't addressed in this study: remember, all their in vivo data are in HGPS mice and in very short-term injury models in normal ones.