Changing Blood Factors in Aging
Cell signaling is carried far and wide in the body via the bloodstream. The molecules involve change significantly with age, including a rise in inflammatory signaling and consequent chronic inflammation. This is a reaction to, or consequence of, forms of damage involved in aging, but it is also a source of significant further dysfunction. That much is demonstrated by plasma dilution studies, in which improved tissue function in several organs is noted as a result of diluting the signals carried by the bloodstream in an aged body.
Traditional indicators of biological age are not always informative and often require extensive and expensive analysis. The study of blood factors is a simple and easily accessible way to assess individual health and supplement the traditional indicators of a person's biological age with new objective criteria. With age, the processes of growth and development, tissue regeneration and repair decline; they are gradually replaced by enhanced catabolism, inflammatory cell activity, and insulin resistance. The number of senescent cells supporting the inflammatory loop rises; cellular clearance by autophagy and mitophagy slows down, resulting in mitochondrial and cellular damage and dysfunction. Monitoring of circulated blood factors not only reflects these processes, but also allows suggesting medical intervention to prevent or decelerate the development of age-related diseases.
Blocking factors that negatively affect lifespan is a reasonable strategy to prevent early disability and prolong the active life of older people. Among such strategies, tested in the clinical practice or which will be translated to the clinical practice, one can highlight overcoming the insulin resistance by diet restriction, increasing FGF21 in blood circulation, pharmacological treatment of insulin resistance (e.g., with dehydroepiandrosterone and metformin), stimulation of tissue repair by GH, oxytocin, GDF11, and TIMP2, vascular regeneration with bFGF, EGF, VEGF, PDGF-AB, and BMP9, preventing the development of "inflammaging" by administering anti-inflammatory molecules, including COX-2 inhibitors, leukotriene receptor antagonists, TIMP2, or other matrix metalloproteinase inhibitors, overcoming the cell senescence by administration of TM5441 analogs, optimizing the autophagy and mitophagy with mTOR inhibitors, with TGF-β inhibitors, antioxidant therapy, reduction of NAD+ exhaustion. The indicators and mechanisms discussed above reflect the natural and pathological aging processes.
The Wyss-Coray article referenced below, indicates that: 75.84% (361) of all proteins associated with aging (529 total targeted proteins) increased expression with age while only 24.16% (115) are associated with a decreased expression. If three times as many age associated components of the proteome increase (75%) as aging progresses and (25%) decrease, It would be a reasonable conclusion that a protocol incorporating a 50% dilution of all plasma proteins, (Conboy article also below,) would result in a net positive impact on aging. There is still of course, the unknown, unknowns.
An all or nothing approach is very unlikely to be optimal, but since the increasing proteins that correlate with aging exists in a ratio of 3 to 1 to the decreasing proteins, the approach of diminishing all proteins would have the net effect of diminishing the increasing proteins in a weighted manor that is three times more impactful than on the decreasing fraction.
This may provide some insights into the mechanism that positively correlates from the Conboy mouse study were: "Specifically, we performed a "neutral" blood exchange (NBE) by replacing the platelet-rich-plasma (PRP), fraction with physiological saline, supplemented with 5% purified commercial (fraction V) albumin. Our data demonstrate that a single NBE suffices to meet or exceed the rejuvenate effects of enhancing muscle repair, reducing liver adiposity and fibrosis, and increasing hippocampal neurogenesis in old mice…"
The Wyss-Coray observation combined with the TPE data from four human subjects also reported in the Conboy paper, adds emphasis to the conclusion of the Conboy's that an effective intervention to ameliorate the detrimental effects of aging is available to older individuals now and should move forward immediately.
"This work improves our understanding of the systemic paradigms of multi-tissue rejuvenation and suggest a novel and immediate use of the FDA approved TPE for improving the health and resilience of older people."
Data mining of human plasma proteins generates a multitude
of highly predictive aging clocks that reflect different aspects
of aging
Benoit Lehallier1,2,3 | Maxim N. Shokhirev4 | Tony Wyss-Coray1,2,3,5 |
Adiv A. Johnson6
Abstract: We previously identified 529 proteins that had been reported by multiple different studies to change their expression level with age in human plasma. In the present study, we measured the q-value and age coefficient of these proteins in a plasma proteomic dataset derived from 4263 individuals. A bioinformatics enrichment analysis of proteins that significantly trend toward increased expression with age strongly implicated diverse inflammatory processes. A literature search revealed that at least 64 of these 529 proteins are capable of regulating life span in an animal model. Nine of these proteins (AKT2, GDF11, GDF15, GHR, NAMPT, PAPPA, PLAU, PTEN, and SHC1) significantly extend life span when manipulated in mice or fish. By performing machine-learning modeling in a plasma proteomic dataset derived from 3301 individuals, we discover an ultra-predictive aging clock comprised of 491 protein entries. The Pearson correlation for this clock was 0.98 in the learning set and 0.96 in the test set while the median absolute error was 1.84 years in the learning set and 2.44 years in the test set. Using this clock, we demonstrate that aerobic-exercised trained individuals have a younger predicted age than physically sedentary subjects. By testing clocks associated with 1565 different Reactome pathways, we also show that proteins associated with signal transduction or the immune system are especially capable of predicting human age. We additionally generate a multitude of age predictors that reflect different aspects of aging. For example, a clock comprised of proteins that regulate life span in animal models accurately predicts age.
Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288913/
Melod Mehdipour1, Colin Skinner1,*, Nathan Wong1,*, Michael Lieb1,*, Chao Liu1, Jessy Etienne1, Cameron Kato1, Dobri Kiprov2, Michael J. Conboy1, Irina M. Conboy1
We replaced half of the plasma in mice with saline containing 5% albumin (terming it a "neutral" age blood exchange, NBE) thus diluting the plasma factors and replenishing the albumin that would be diminished if only saline was used.
Abstract: Our data demonstrate that a single NBE suffices to meet or exceed the
rejuvenative effects of enhancing muscle repair, reducing liver adiposity and fibrosis, and increasing hippocampal neurogenesis in old mice, all the key outcomes seen after blood heterochronicity. Comparative proteomic analysis on serum from NBE, and from a similar human clinical procedure of therapeutic plasma exchange (TPE), revealed a molecular re-setting of the systemic signaling milieu, interestingly, elevating the levels of some proteins, which broadly coordinate tissue maintenance and repair and promote immune responses. Moreover, a single TPE yielded functional blood rejuvenation, abrogating the typical old serum inhibition of progenitor cell proliferation. Ectopically added albumin does not seem to be the sole determinant of such rejuvenation, and levels of albumin do not decrease with age nor are increased by NBE/TPE. A model of action (supported by a large body of published data) is that significant dilution of autoregulatory proteins that crosstalk to multiple signaling pathways (with their own feedback loops) would, through changes in gene expression, have long-lasting molecular and functional effects that are consistent with our observations. This work improves our understanding of the systemic paradigms of multi-tissue rejuvenation and suggest a novel and immediate use of the FDA approved TPE for improving the health and resilience of older people.
This is a follow-up to Michael's comments on Conboy saline results and protein ratios (upregulated outnumbering downregulated by 3 to 1). As replacing "young" proteins or modulating genes to normalize their expression and thereby change the protein ratios to verify this normalized expression is some ways off, I looked for methods that might partly mimic Conboy's 2020 results. As a result, and partly coincidental, I started platelet donation early April 2021. In Florida, my local blood bank asked for platelet donation which are needed by cancer patients. After looking into it found that I could donate platelets every 2 weeks and plasma every 4 weeks. I settled on double platelets (DP) every two weeks. DP removes 346 mls of plasma. Every 4 weeks I can add additional plasma donation to bring total plasma removal to 540 mls. So, every 4 weeks I manage to remove about 880 mls out of my roughly 3000 mls of plasma, i.e.about 28%. They do not replace the volume with saline or albumin. The body replaces the volume in about 48 hours. My albumin levels have stayed normal. I'll be continuing this for the next year to so.