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Cited by 115Genetics, Aging, and Longevity in Model OrganismsTelomeres, Telomerase, and SenescencePluripotent Stem Cells Research

The DOI matches its Crossref record; 86 of the 86 references it cites were found in a registry or an index; 73 of the 126 sources its claims cite were checked for support.

Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin

Open access
Mehdipour, Melod, Skinner, Colin, Wong, Nathan, Lieb, Michael, Liu, Chao, Etienne, Jessy, Kato, Cameron, Kiprov, Dobri, Conboy, Michael J., Conboy, Irina M.·2020·Aging
DOI 10.18632/aging.103418PMC PMC7288913
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Abstract

Heterochronic blood sharing rejuvenates old tissues, and most of the studies on how this works focus on young plasma, its fractions, and a few youthful systemic candidates. However, it was not formally established that young blood is necessary for this multi-tissue rejuvenation. Here, using our recently developed small animal blood exchange process, 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. 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.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Replacing half of old mouse blood plasma with saline containing 5% albumin—termed neutral blood exchange (NBE)—rejuvenated muscle, liver, and hippocampal neurogenesis without young blood. A similar human therapeutic plasma exchange (TPE) reset the serum proteome and removed old-serum inhibition of myogenic progenitor proliferation.

Key findings

  • A single NBE improved old mouse muscle repair, reduced fibrosis, and increased minimum Feret diameter of de novo myofibers to levels not significantly different from young: OO vs ONBE regenerative index p = 0.000001, fibrotic index p = 0.000048, Feret diameter p = 3.04346E-05; YY vs YNBE was non-significant for regeneration (p = 0.4014) and fibrosis (p = 0.1712), though Feret diameter differed (p = 0.009).
  • NBE increased hippocampal neurogenesis in old mice by ~8-fold (ONBE vs OO p = 0.0000145), not significantly different from YY (p = 0.15235), with no significant reduction in young mice (YNBE trend ~44% increase, p = 0.20123).
  • NBE reduced old liver adiposity and fibrosis: adiposity OO-ONBE p = 0.0004, YY-ONBE p = 0.04; fibrosis OO-ONBE p = 0.00001, YY-ONBE p = 0.012; young mice did not worsen.
  • Human TPE removed old-serum inhibition of myoblast proliferation: post-TPE serum increased BrdU+ cells in every subject (p = 0.011, <0.0001, <0.0001, 0.0039), including with 4% HSA. Proteomics showed NBE/TPE changed systemic proteins—often elevating angiogenic, immune, and growth-factor proteins—while albumin was not the sole determinant and did not decrease with age or increase net after NBE/TPE.

Methods

  • Young (2–4 months) and old (22–24 months) male C57/B6 mice underwent a single NBE replacing 50% platelet-rich plasma with saline + 5% mouse albumin while returning blood cells; controls were isochronic young–young (YY) and old–old (OO) exchanges. Analyses were at 6 days after exchange; N = 4 YY/OO, N = 6 YNBE, N = 7 ONBE for neurogenesis, and N = 8 for liver measures.
  • Muscle repair was assayed after cardiotoxin injury by H&E, eMyHC, fibrosis, and minimum Feret diameter; liver by Oil Red-O and Masson’s trichrome/albumin; brain by Ki67+ cells in the subgranular zone. Human samples came from four old individuals (65–70 years) before and after TPE; primary myoblasts were cultured with 4% pre/post-TPE serum ± 4% HSA and BrdU incorporation quantified.
  • Serum proteomics used antibody arrays for 308 mouse and 506 human proteins, with t-SNE clustering and heatmaps; Western blotting and antioxidant assays were also performed. Statistics used two-tailed t-tests with p ≤ 0.05, and power analysis based on effect size and variance indicated N = 4 could yield power ≥ 0.8.

Limitations

  • The paper states that it does not exclude contributions from young blood factors, shared young organs, or environmental enrichment; whether NBE/TPE improve neuronal differentiation, neuroplasticity, cognition, broader metabolic health, or other tissues remains undetermined. It also notes the human pilot longitudinal sample is small, the dilution model is one possible mechanism, albumin is not the only determinant, and YNBE mice showed higher variation across tissues.
  • Evident from the text: mouse cohorts were small (N = 4–8), human TPE data involved only four old individuals and pre/post serum assays without clinical outcomes, proteomic arrays covered a limited set of proteins, and the mouse experiments used only male C57/B6 mice.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.18632/aging.103418

Cites

86 of 86 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

73 of 126 cited sources checked · 19 supported · 4 flagged · accuracy not yet measured

  • Premisecitation

    In people, albumin levels correlate with disease, nutrition, and socio-economic status rather than chronological age.

    “In people, albumin levels correlate with disease, nutrition, and socio-economic status rather than chronological age”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [21] Gardner, 1989, Effect of aging on serum albumin., J Am Geriatr Soc source
    • cites [22] Jones, 2016, Age and sex variation in serum albumin concentration: an observational study., Ann Clin Biochem source

      The Aggregated data section reports that mean serum albumin concentration peaks around age 20 and then decreases with increasing age, contrary to the claim’s dismissal of chronological age. The Introduction says albumin is used to monitor disease and assess nutritional status, but our copy does not establish a correlation with socio-economic status. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [23] Kondo, 2016, Serum albumin levels and economic status in Japanese older adults., PLoS One source

      The Introduction says decreased serum albumin is strongly associated with aging, directly contradicting the claim’s ‘rather than chronological age’ distinction. The Discussion also links albumin to disease and malnutrition, and the paper examines its association with economic status; those points do not negate the stated association with aging. Our copy provides section labels but no page numbers. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [24] Shimoyama, 2017, Aging and death-associated changes in serum albumin variability over the course of chronic hemodialysis treatment., PLoS One source

      The Discussion (Albumin variability; page unavailable) says mean albumin levels were strongly associated with age, while albumin variability was poorly associated with chronological age. Results (Mutual associations among parameters of albumin dynamics and demographics; page unavailable) reports a significant negative correlation between age and mean albumin level (r = −0.571). The claim appears to apply the paper’s finding about variability to albumin levels; the cited passages do not establish a correlation with socioeconomic status. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Heterochronic blood sharing rejuvenates old tissues.

    “Heterochronic blood sharing rejuvenates old tissues”
    • Also stated in: § INTRODUCTION · plain
      “The general conclusion of these studies was that the old partners had better health and/or repair of cartilage, muscle, liver, brain, spinal cord, kidneys, bone, skin, etc., and often the young animals experienced premature aging of their respective tissues [1, 3, 4, 6–8].”
    Quote in the paperSubstantial claim2 of 6 sources checked
    • cites [1] Rando, 2005, Rejuvenation of aged progenitor cells by exposure to a young systemic environment., Nature source
    • cites [3] Rando, 2012, Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches., Cell Cycle source
    • cites [4] Rando, 2013, Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity., Aging Cell source
    • cites [6] Rando, 2005, Aging, stem cells and tissue regeneration: lessons from muscle., Cell Cycle source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [7] Rebo, 2015, Systemic problems: a perspective on stem cell aging and rejuvenation., Aging (Albany NY) source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [8] Rando, 2007, Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis., Science source
  • Premisecitation

    Young mice exhibit rapid and significant decline in hippocampal neurogenesis, agility, learning and liver regeneration after a single exchange with old blood.

    “More recently, blood exchange studies demonstrated that blood heterochronicity alone, without the parabiotic sharing of organs or environment, quickly rejuvenates muscle and liver, but interestingly, not hippocampal neurogenesis or cognitive performance of old mice, and that young mice exhibit rapid and significant decline in hippocampal neurogenesis, agility, learning and liver regeneration after”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Conboy, 2016, A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood., Nat Commun source

      The Results sections on hippocampal neurogenesis and liver report declines in young mice after one exchange with old blood. The Results section on performance reports a lower four-limb hanging index, a test combining strength, endurance, coordination and learning. It does not establish separate, significant declines in agility and learning; the Discussion presents cognitive decline as an interpretation of the performance result. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Mouse primary myoblasts can be used for determining the effects of proteins secreted by human cells on myogenic cell proliferation and differentiation.

    “We previously established that mouse primary myoblasts can be used for determining the effects of the proteins that are secreted by human cells on myogenic cell proliferation and differentiation [15, 19, 20].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [15] Schaffer, 2015, Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal., Oncotarget source

      The Experimental Procedures (Cell culture; page not available) describe isolating and culturing primary mouse myoblasts, and the Results (Rejuvenation of myogenesis and neurogenesis by genetic attenuation of TGF-β signaling; page not available) measure proliferation of mouse myogenic precursors. These passages do not establish their use to test proteins secreted by human cells or effects on myogenic differentiation. (LLM, conf=0.81)

      Experimental — accuracy not yet measured
    • cites [19] Conboy, 2011, Embryonic anti-aging niche., Aging (Albany NY) source
    • cites [20] Conboy, 2013, hESC-secreted proteins can be enriched for multiple regenerative therapies by heparin-binding., Aging (Albany NY) source
  • Premisecitation

    The original work on rejuvenation of old animals and aging of young through heterochronic parabiosis showed effects not only for skeletal muscle, but also for liver and brain-hippocampal neurogenesis.

    “In the original work on rejuvenation of old animals and aging of young through heterochronic parabiosis, the effects were shown not only for skeletal muscle, but also for the liver and brain-hippocampal neurogenesis [1, 7].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [1] Rando, 2005, Rejuvenation of aged progenitor cells by exposure to a young systemic environment., Nature source
    • cites [7] Rebo, 2015, Systemic problems: a perspective on stem cell aging and rejuvenation., Aging (Albany NY) source
  • Probably not a substantial claim. 29
  • It may state two separate claims as one. 40

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Exchange of old mice with young blood diminishes tissue levels of B2M.

    “and an exchange of old mice with young blood diminishes the tissue levels of B2M [9].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [9] Conboy, 2016, A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood., Nat Commun source

      The Results section (“B2M and TGF-beta as mechanisms are tissue specific”) explicitly reports no decline of B2M in the hippocampi or whole brains of old mice exchanged with young blood. It also says B2M differences between old mice exchanged with old versus young blood were undetectable in the muscle regions examined, contrary to the claimed decrease in tissue B2M. (LLM, conf=0.91)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    Blood exchange studies demonstrated that blood heterochronicity alone, without parabiotic sharing of organs or environment, quickly rejuvenates muscle and liver.

    “More recently, blood exchange studies demonstrated that blood heterochronicity alone, without the parabiotic sharing of organs or environment, quickly rejuvenates muscle and liver, but interestingly, not hippocampal neurogenesis or cognitive performance of old mice, and that young mice exhibit rapid and significant decline in hippocampal neurogenesis, agility, learning and liver regeneration after”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Conboy, 2016, A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood., Nat Commun source

  • It may state two separate claims as one.

    Premisecitation

    Blood Brain Barrier becomes leaky with age and serum albumin crosses it and is found in cerebro-spinal-fluid of older individuals in positive correlation with age and certain types of dementias.

    “With respect to reaching neural cells in vivo, Blood Brain Barrier becomes leaky with age [31, 32] and serum albumin crosses it and is found in cerebro-spinal-fluid of older individuals in a positive correlation with age and with certain types of dementias [33].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [31] Zlokovic, 2015, Blood-brain barrier breakdown in the aging human hippocampus., Neuron source

      The Results sections report age-dependent BBB leakage in the hippocampus and a higher CSF/plasma albumin ratio in people with mild cognitive impairment than in age-matched controls. They do not report that CSF albumin itself rises with age or correlates positively with particular types of dementia; the reported albumin-ratio correlation is with hippocampal BBB permeability. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [32] Wharton, 2018, Age-associated changes in the blood-brain barrier: comparative studies in human and mouse., Neuropathol Appl Neurobiol source
    • cites [33] Simonsen, 2020, Cerebrospinal fluid/plasma albumin ratio as a biomarker for blood-brain barrier impairment across neurodegenerative dementias., J Alzheimers Dis source

  • It may state two separate claims as one.

    Premisecitation

    Neurogenesis in the subgranular zone of the hippocampus continues throughout adult life, dramatically declines with advanced age and is influenced by blood heterochronicity.

    “Neurogenesis in the subgranular zone (SGZ) of the hippocampus continues throughout adult life, dramatically declines with advanced age and is influenced by blood heterochronicity [7, 9, 14, 26].”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [7] Rebo, 2015, Systemic problems: a perspective on stem cell aging and rejuvenation., Aging (Albany NY) source

      The Prologue’s Figure 1 caption reports a marked reduction in hippocampal neurogenesis in old mice and shows that heterochronic pairing changes neural stem-cell proliferation. It examines the dentate gyrus, but does not specifically identify the subgranular zone or establish that neurogenesis continues throughout adult life. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [9] Conboy, 2016, A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood., Nat Commun source

      The Results section, “Hippocampal neurogenesis responds to old blood and injury” (page unavailable), reports that a single exchange with old blood severely decreased SGZ neurogenesis in young mice. The passages support an influence of heterochronic blood but do not establish that SGZ neurogenesis continues throughout adult life or quantify a dramatic decline with advanced age. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [14] Conboy, 2019, Rejuvenation of brain, liver and muscle by simultaneous pharmacological modulation of two signaling determinants, that change in opposite directions with age., Aging (Albany NY) source
    • cites [26] Gage, 1996, Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation., J Neurosci source

      The Discussion (page not indicated) reports ongoing neurogenesis in adult rats and a steep decline with age: newborn cells remained detectable in senescent rats, but aged rats had only 10–17% of the six-month-old level. The paper does not address blood heterochronicity, so that part of the sentence is not supported by this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Liver adiposity and fibrosis are known to increase with age and to be influenced by blood heterochronicity.

    “Liver adiposity and fibrosis are known to increase with age and to be influenced by blood heterochronicity [1, 9, 14, 35–38].”
    Quote in the paperSubstantial claim5 of 7 sources checked
    • cites [1] Rando, 2005, Rejuvenation of aged progenitor cells by exposure to a young systemic environment., Nature source
    • cites [9] Conboy, 2016, A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood., Nat Commun source
    • cites [14] Conboy, 2019, Rejuvenation of brain, liver and muscle by simultaneous pharmacological modulation of two signaling determinants, that change in opposite directions with age., Aging (Albany NY) source
    • cites [35] Loria, 2014, Nonalcoholic fatty liver disease and aging: epidemiology to management., World J Gastroenterol source

      Table 1 (page unavailable) reports increased liver fibrosis with aging, but also a reduced percentage of fat on liver biopsy, rather than increased liver adiposity. The Background says NAFLD mainly affects middle-aged and elderly people. No passage in our copy links either liver change to blood heterochronicity (searched: heterochronicity, heterochronic parabiosis, young blood). (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [36] Nüssgen, 1986 source
    • cites [37] Leclercq, 2016, Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling., Aging (Albany NY) source

      The Discussion reports more severe fibrosis in older mice after the same profibrotic treatment and describes increased susceptibility to fibrosis with age. The Introduction discusses progression from steatosis to fibrosis in older patients with fatty liver disease, but neither passage establishes that liver adiposity increases with age; the paper also does not address blood heterochronicity. Page numbers were not provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [38] Barnhoorn, 2017, Cellular senescence drives age-dependent hepatic steatosis., Nat Commun source

      The Results section (‘DR protects against liver fat deposition’; page unavailable) reports progressive hepatic steatosis with age in mice. The Discussion discusses fibrosis as a possible consequence of chronic steatosis, but does not establish that fibrosis itself increases with age. The paper does not report that blood heterochronicity influences either outcome. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    The general conclusion of heterochronic parabiosis studies was that old partners had better health and/or repair of cartilage, muscle, liver, brain, spinal cord, kidneys, bone, skin, etc.

    “The general conclusion of these studies was that the old partners had better health and/or repair of cartilage, muscle, liver, brain, spinal cord, kidneys, bone, skin, etc.”
    Quote in the paperSubstantial claim4 of 6 sources checked
    • cites [1] Rando, 2005, Rejuvenation of aged progenitor cells by exposure to a young systemic environment., Nature source
    • cites [3] Rando, 2012, Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches., Cell Cycle source

      The ‘Heterochronic Parabiotic Studies of Stem Cell Aging’ section reports improved regeneration in old muscle and liver and discusses effects in brain; ‘Is Aging of Other Adult Tissues a Stem Cell Paradigm?’ also reports evidence of rejuvenated bone in old parabionts. Our copy does not substantiate the claimed improvements in cartilage, spinal cord, kidneys, or skin. Page numbers were not available in the indexed passages. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [4] Rando, 2013, Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity., Aging Cell source

      The Historical Perspective section reports benefits to older parabionts in longevity and tissue function, and says aged stem cells regained regenerative potential when exposed to youthful influences (page unavailable). It does not report improved health or repair across the full list of cartilage, muscle, liver, brain, spinal cord, kidneys, bone, and skin. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [6] Rando, 2005, Aging, stem cells and tissue regeneration: lessons from muscle., Cell Cycle source

      In “Lessons from Muscle” (page unavailable), the paper reports markedly improved regeneration of aged muscle in old mice paired with young mice, and enhanced liver progenitor-cell proliferation. It does not report improved overall health or repair of cartilage, brain, spinal cord, kidneys, bone, or skin in the old partners; its suggestion that effects may extend beyond muscle is not evidence for those specific tissues. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [7] Rebo, 2015, Systemic problems: a perspective on stem cell aging and rejuvenation., Aging (Albany NY) source

      The Prologue reports better cartilage health in old rats paired with young rats and rejuvenation of stem cells in muscle, brain/hippocampus, and liver. The paper does not report improved repair of spinal cord, kidneys, bone, or skin in old partners; mentioning young kidneys as a possible benefit to the pair is not evidence of kidney repair. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [8] Rando, 2007, Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis., Science source

  • It may state two separate claims as one.

    Interpretationcitation

    Dilution will diminish expression of age-elevated autoinducers and feedback will decrease their levels for a prolonged time.

    “where dilution will diminish their expression and feedback will decrease the levels for a prolonged time [48–56].”
    Quote in the paperSubstantial claim3 of 9 sources checked
    • cites [48] Roberts, 1990, Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex., Mol Cell Biol source
    • cites [49] Absher, 1993, Auto-induction of transforming growth factor-beta in human lung fibroblasts., Am J Respir Cell Mol Biol source
    • cites [50] Ueno, 1994, Autoinduction of activin genes in early xenopus embryos., Biochem J source

      The ‘Autoinduction of activin genes in isolated animal caps’ section reports dose-dependent induction of activin mRNA by added activin, supporting a concentration-dependent autoinduction mechanism. It does not test dilution of age-elevated autoinducers or show that feedback keeps their levels low for a prolonged time. In its time-course experiment, a brief activin exposure was sufficient to produce mRNA accumulation measured 36 hours after the activin was washed away. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [51] Winokur, 1995, Autoinduction of mRNA and protein expression for transforming growth factor-beta S in cultured cardiac cells., J Mol Cell Cardiol source
    • cites [52] Suter-Crazzolara, 1999, Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1)., Gene source
    • cites [53] Knöchel, 1998, Structural and functional analysis of the BMP-4 promoter in early embryos of xenopus laevis., Mech Dev source

      Section 2.4 reports a positive BMP-4 auto-regulatory loop and reduced promoter activity when BMP signaling is blocked, supporting the feedback component. The paper studies early Xenopus embryos; it does not show that dilution reduces expression of age-elevated autoinducers or that their levels remain low for a prolonged time. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [54] Knöchel, 2006, XBP1 forms a regulatory loop with BMP-4 and suppresses mesodermal and neural differentiation in xenopus embryos., Mech Dev source

      Section 2.4 describes a regulatory loop among xXBP1, BMP-4, and Xvent-2 in Xenopus embryos, but does not examine dilution or whether it causes a prolonged decrease in expression. Searches for dilution, autoinducers, aging, and prolonged feedback effects found no passage addressing that claim. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [55] Unterman, 2007, Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors., Am J Physiol Cell Physiol source
    • cites [56] Hendry, 2009, Tgf-beta auto-induction and connective tissue growth factor expression in human renal tubule epithelial cells requires n-ras., Nephron Exp Nephrol source
    • The authors state this as an assumption: In the Figure 6 model, protein A induces itself and C, A represses B, and C represses A.

  • It may state two separate claims as one.

    Premisecitation

    Elevation of Tomoreguilin-1 by TPE is expected to have positive effects; it antagonizes Nodal and Junk signaling, combats cardiac hypertrophy, is needed for CNS formation and maintenance, and is neuroprotective by binding toxic Alzheimer's Disease amyloid beta.

    “Similarly, a general positive effects are expected from the elevation by TPE of Tomoreguilin-1, which antagonizes Nodal and Junk signaling, was shown to combat cardiac hypertrophy [81], to be needed for CNS formation and maintenance [82], and to be neuroprotective, by binding toxic Alzheimer’s Disease amyloid beta [83].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [81] Zhang, 2015, Tomoregulin-1 prevents cardiac hypertrophy after pressure overload in mice by inhibiting TAK1-JNK pathways., Dis Model Mech source
    • cites [82] Martens, 2000, Expression of the follistatin/EGF-containing transmembrane protein M7365 (tomoregulin-1) during mouse development., Mech Dev source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [83] Jin, 2015, Tomoregulin (TMEFF2) binds alzheimer’s disease amyloid-β (aβ) oligomer and AβPP and protects neurons from Aβ-induced toxicity., J Alzheimers Dis source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Interpretationreasoning

    Entire pathways such as MAPK are no longer hijacked for non-canonical induction of TGF-beta, Smad1, and inflammation but instead engage in productive signaling by their cognate ligands, promoting tissue health, regeneration, and homeostatic production of cytokines and growth factors.

    “entire pathways (MAPK, for example) are no longer hijacked for non-canonical induction of TGF-beta, Smad1, and inflammation [57, 58], but instead engage in productive signaling by their cognate ligands, promoting tissue health, regeneration and homeostatic production of cytokines and growth factors [59–61] (with their own positive feed-backs), as we observe.”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [57] Mulder, 2000, Role of ras and mapks in TGFbeta signaling., Cytokine Growth Factor Rev source
    • cites [58] Chi, 2003, Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and ras signaling pathways., Oncogene source
    • cites [59] Quisel, 2014, Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis., Nat Med source
    • cites [60] Chen, 2004, Suppression of matrix metalloproteinase-9 transcription by transforming growth factor-beta is mediated by a nuclear factor-kappaB site., Biochem J source

      Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [61] Hu, 2009, TGFbeta inhibits GM-CSF-induced phosphorylation of ERK and MEK in human myeloid leukaemia cell lines via inhibition of phosphatidylinositol 3-kinase (PI3-k)., Cell Prolif source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • The authors state this as an assumption: In the Figure 6 model, protein A induces itself and C, A represses B, and C represses A.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Improved tissue maintenance is typically accompanied by healthy remodeling.

    “Finally, improved tissue maintenance is typically accompanied by a healthy remodeling [77, 84, 85]”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [77] Sheardown, 2004, Growth factors in the anterior segment: role in tissue maintenance, wound healing and ocular pathology., Exp Eye Res source
    • cites [84] Keski-Oja, 1997, Growth factors in the extracellular matrix., FASEB J source
    • cites [85] Wysocki, 2009, Interactions between extracellular matrix and growth factors in wound healing., Wound Repair Regen source

      In OVERVIEW OF THE ECM (page unavailable), the paper says fibroblasts remodel collagen to restore tissue integrity, linking remodeling with tissue repair. It does not establish that improved tissue maintenance is typically accompanied by healthy remodeling across tissues; its discussion concerns wound healing, and its proposed improvement in scar quality is explicitly theoretical. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Immune regulators promote better surveillance and wound clearance in multiple tissues.

    “Immune regulators promote better surveillance and wound clearance in multiple tissues [75, 76].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [75] Tartar, 2018, Immunology of wound healing., Curr Dermatol Rep source

      The Inflammation section says macrophages clear microbes and cellular debris from cutaneous wounds, supporting the wound-clearance portion. The paper does not establish that immune regulators improve surveillance and wound clearance across multiple tissues; its review focuses on skin wounds. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [76] Moser, 2018, Peripheral tissue chemokines: homeostatic control of immune surveillance T cells., Trends Immunol source

      The Highlights (p. 27) say peripheral-tissue chemokines orchestrate local immune surveillance, and the Concluding Remarks (p. 13) describe their role in retaining surveillance cells in tissues such as skin and mucosal epithelia. Our copy does not say they promote wound clearance; its discussion of tissue recovery concerns the resolution of infection and inflammation, not wounds. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Interpretationcitation

    When ligand levels diminish, attenuators also diminish and receptors increase; signaling re-boot induces negative regulators, as observed for follistatin and follistatin-like, secondarily diminishing the intensity of age-elevated pathways.

    “When the levels of ligand(s) diminish, attenuators also diminish, and receptor(s) increase [62, 63]; signaling re-boot induces negative regulators, as we observed for follistatin and follistatin-like, secondarily diminishing the intensity of age-elevated pathways [64–66].”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [62] Chen, 2018, Feedback regulation of TGF-β signaling., Acta Biochim Biophys Sin (Shanghai) source

      The section “Feedback on the Receptors” (page unavailable) says TGF-β-family cytokines induce inhibitory Smad6 and Smad7, establishing negative feedback loops. That supports the general claim that signaling can induce regulators that limit signaling. The cited paper does not establish the claimed effect on age-elevated pathways; the follistatin observation is presented as the citing authors’ own. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [63] Sharma, 2006, Myostatin auto-regulates its expression by feedback loop through Smad7 dependent mechanism., J Cell Physiol source
    • cites [64] Rimokh, 2002, Transcription activation of FLRG and follistatin by activin A, through smad proteins, participates in a negative feedback loop to modulate activin a function., Oncogene source
    • cites [65] van den Hoff, 2011, The BMP antagonist follistatin-like 1 is required for skeletal and lung organogenesis., PLoS One source

      The Introduction identifies follistatin-like 1 as a BMP inhibitor, supporting its description as a negative regulator. The paper studies developmental organogenesis; it does not show that restarting signaling induces follistatin or follistatin-like 1, or that either reduces the intensity of age-elevated pathways. The preceding ligand-and-receptor clause is attached to different citations. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [66] Wrana, 2000, Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation., Mol Cell source
    • The authors state this as an assumption: In the Figure 6 model, protein A induces itself and C, A represses B, and C represses A.

  • Probably not a substantial claim.

    Premisecitation

    Modulation of multiple key cell-fate regulatory pathways, including attenuation of pSmad2,3 signaling by follistatin, is important for productive cell proliferation and regeneration in skeletal muscle, heart, and generally throughout the body.

    “Modulation of multiple key cell-fate regulatory pathways, including attenuation of pSmad2,3 signaling by follistatin, is important for productive cell proliferation and regeneration in skeletal muscle, heart and generally, throughout the body [77–79].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [77] Sheardown, 2004, Growth factors in the anterior segment: role in tissue maintenance, wound healing and ocular pathology., Exp Eye Res source
    • cites [78] Deuel, 1991, Growth factor-induced acceleration of tissue repair through direct and inductive activities in a rabbit dermal ulcer model., J Clin Invest source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [79] Werner, 2017, Fibroblast growth factors: key players in regeneration and tissue repair., Development source

  • It may state two separate claims as one.

    Findingown data

    A single TPE yields functional blood rejuvenation, abrogating the typical old serum inhibition of progenitor cell proliferation.

    “Moreover, a single TPE yielded functional blood rejuvenation, abrogating the typical old serum inhibition of progenitor cell proliferation.”
    • Also stated in: § INTRODUCTION · plain
      “Interestingly, single TPE procedure removed this inhibition and allowed for robust proliferation of myogenic progenitors that were cultured with the PostTPE old serum”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The ONBE proteome became significantly different from OO and regained some similarities to the YY proteome.

    “Multi-dimensional t-SNE analyses and Heatmapping of these data revealed that the ONBE proteome became significantly different from OO and regained some similarities to the YY proteome (Figure 5A–5C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Muscle fibrosis was not different between YY and young control mice that did not experience blood exchange or OO and old control mice.

    “Muscle fibrosis was not different between YY and young control mice that did not experience blood exchange or OO and old control mice”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    In the absence of robust phenotypes, if two phenomena are detected as the same or have very modest effect, with high enough N the statistical power will strictly increase.

    “In contrast, in the absence of robust phenotypes, if two phenomena are detected as the same or have very modest effect, with high enough N the statistical power will strictly increase.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Ectopic albumin enhanced NPC proliferation by itself in the absence of serum and improved NPC proliferation when old serum was present.

    “Interestingly, in contrast to the lack of effects on myogenic cells, ectopic albumin enhanced NPC proliferation by itself – in the absence of serum and improved NPC proliferation when old serum was present in the cultures (Supplementary Figure 3B).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    HSA neither rescued proliferation of PreTPE myoblast cultures nor added to proliferation of Post-TPE cultures.

    “HSA neither rescued the proliferation of PreTPE myoblast cultures, nor added to the proliferation of the Post-TPE cultures (Figure 2).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Regeneration was slightly better in YY than Y and in OO than O cohorts.

    “regeneration was slightly better in YY than Y and in OO than O cohorts”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    YY/Young cohorts had higher regeneration and lower fibrosis than OO/Old cohorts.

    “YY/Young cohorts had higher regeneration and lower fibrosis than OO/Old cohorts (Supplementary Figure 1).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Human old before TPE was robustly different from old after TPE, establishing a significant change in human circulatory proteins one month after a single TPE procedure.

    “As true for the mouse data, human O Before TPE was also robustly different from O After TPE, establishing a significant change in the composition of human circulatory proteins one month after a single procedure (Figure 5D, 5E; and Supplementary Table 1).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    VCAM-1 levels were similar between young and old serum (p=0.953), confirmed by Western blotting.

    “We observed similar levels of VCAM-1 (p=0.953) between young and old serum which was confirmed by Western Blotting (Supplementary Figure 5)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    Blood heterochronicity alone does not rejuvenate hippocampal neurogenesis or cognitive performance of old mice.

    “More recently, blood exchange studies demonstrated that blood heterochronicity alone, without the parabiotic sharing of organs or environment, quickly rejuvenates muscle and liver, but interestingly, not hippocampal neurogenesis or cognitive performance of old mice, and that young mice exhibit rapid and significant decline in hippocampal neurogenesis, agility, learning and liver regeneration after”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Conboy, 2016, A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood., Nat Commun source

  • It may state two separate claims as one.

    Study design and conductown data

    In work on repair of injured muscle, four independent characterizations of adult myogenesis (regenerative index, fibrosis, minimum Feret diameter, and myogenic proliferation) showed data agreement between all and between mouse and human studies.

    “In work on repair of injured muscle, we performed four independent characterizations of adult myogenesis: regenerative index, fibrosis, minimum Feret diameter and myogenic proliferation with data agreement between all and between the mouse and human studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Premisecitation

    The effects of heterochronic blood exchange were studied with all three germ layers derived tissues.

    “Similarly, the effects of heterochronic blood exchange were studied with all these three germ layers derived tissues [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Conboy, 2016, A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood., Nat Commun source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Each assay on each sample and tissue was done in multiple replicates.

    “Each assay on each sample and tissue was done in multiple replicates.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    There is a procedure for human patients analogous to NBE, called Therapeutic Plasma Exchange (TPE), which is FDA approved and routinely used in the clinic.

    “there is a procedure for human patients analogous to NBE, where most of the plasma is replaced by physiologic solution supplemented with commercial human albumin, called Therapeutic Plasma Exchange, TPE, which is FDA approved and routinely used in the clinic [16–18].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [16] Kiprov, 2003, Therapeutic apheresis delivery systems in the US., Transfus Apher Sci source
    • cites [17] Hunnicutt, 2001, Adverse reactions associated with mobile therapeutic apheresis: analysis of 17,940 procedures., J Clin Apher source
    • cites [18] Hofmann, 2003, Plasmapheresis in immunologically mediated polyneuropathies., Ther Apher Dial source

  • It may state two separate claims as one.

    Premisecitation

    Infusions of albumin into the brain were deleterious, causing neuro-inflammation, excessive TGF-beta1 and neuronal dysfunctions.

    “Moreover, in direct test, infusions of albumin into the brain were deleterious: causing neuro-inflammation, excessive TGF-beta1 and neuronal dysfunctions [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Preininger, 2019, Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction., Sci Transl Med source

  • It may state two separate claims as one.

    Study design and conductown data

    In hippocampal neurogenesis studies, 6-7 independent start-to-finish experiments with each cohort were performed and were in agreement with in vitro studies with neural precursor cells.

    “In the studies of hippocampal neurogenesis, we performed 6-7 independent start-to-finish experiments with each cohort and these are in agreement with our in vitro studies with neural precursor cells.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    These findings are most consistent with the conclusion that the age-altered systemic milieu inhibits the health and repair of multiple tissues in old mice, and also exerts a dominant progeric effect on the young partners in parabiosis or blood exchange.

    “These findings are most consistent with the conclusion that the age-altered systemic milieu inhibits the health and repair of multiple tissues in the old mice, and also exerts a dominant progeric effect on the young partners in parabiosis or blood exchange.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Proteins of low, medium and high levels are detected with high sensitivity in the antibody array proteomics set-up.

    “Proteins of low, medium and high levels are detected with high sensitivity (high dynamic range) in this set-up, as demonstrated by Figure 5, Supplementary Figure 4, and Supplementary Table 1.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    In our work total levels of albumin were not altered, but rather replenished from those diminished by NBE/TPE, thus negative effects on the brain are not anticipated.

    “In our work the total levels of albumin were not altered, but rather replenished from those diminished by NBE/TPE, thus negative effects on the brain are not anticipated.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    These results establish broad tissue rejuvenation by a single replacement of old blood plasma with physiologic fluid: muscle repair was improved, fibrosis was attenuated, inhibition of myogenic proliferation was switched to enhancement, liver adiposity and fibrosis were reduced, and hippocampal neurogenesis was increased.

    “Summarily, these results establish broad tissues rejuvenation by a single replacement of old blood plasma with physiologic fluid: muscle repair was improved, fibrosis was attenuated, and inhibition of myogenic proliferation was switched to enhancement; liver adiposity and fibrosis were reduced; and hippocampal neurogenesis was increased.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The NBE procedure, replacing half of the plasma with saline containing 5% albumin, is a neutral age blood exchange that does not itself introduce rejuvenative factors beyond dilution of plasma factors and albumin replenishment.

  • It may state two separate claims as one.

    Study design and conductown data

    In liver studies, two characterizations of liver health (adiposity and fibrosis) were performed, fibrosis by two independent methods, with data agreement in 8 independent start-to-finish experiments with each cohort.

    “In liver studies, we performed two characterizations of liver health: adiposity and fibrosis, latter was assayed by two independent methods; the data agreement was seen in 8 independent start-to-finish experiments with each cohort.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    Based on power analysis and preliminary work with N=3, a Power of 0.8 and higher and robust significance of conclusions was obtainable with N=4.

    “Based on the above analysis and preliminary YY, OO, YNBE and ONBE work with N=3 for each cohort, a Power of 0.8 and higher and robust significance of our conclusions was obtainable with N=4.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given

    Ectopic albumin might promote enhanced immunity in NBE/TPE, particularly after multiple in vivo procedures.

    “ectopic albumin might promote enhanced immunity in NBE/TPE, particularly after multiple in vivo procedures.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    The data suggest better myogenesis, angiogenesis, and tissue vascularization in old animals.

    “Better myogenesis, angiogenesis and tissue vascularization in the old are also suggested by our data”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Human blood work was done under the approved biological use authorization protocol.

    “Human blood work was done under the approved biological use authorization protocol”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationreasoning

    NBE is predicted to promote stronger rejuvenation than an Alk5 inhibitor because the inhibitor attenuates just one branch of one pathway.

    “NBE is also predicted to promote stronger rejuvenation than an Alk5 inhibitor, as that attenuates just one branch of one pathway”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: In the Figure 6 model, protein A induces itself and C, A represses B, and C represses A.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    For each experiment, sample sizes of n = 4 or greater were determined using power analysis, IACUC considerations, and effect size, variance, and N that yielded power of 0.8 in previous experimental studies (2005-2020).

    “Sample sizes of n = 4 or greater were determined for each experiment based on Power Analysis, IACUC considerations, and based on Effect Size, Variance and N that yielded Power of 0.8 in previous experimental studies (2005-2020).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    TPE, a currently approved FDA procedure, promotes molecular and functional rejuvenation of the blood in older people, with improved proteomic profile and support for myogenic responses.

    “Importantly, it shows that a currently approved FDA procedure promotes molecular and functional rejuvenation of the blood in older people, with improved proteomic profile and support for myogenic responses.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    The replacement albumin was >95% pure by manufacturer's analysis.

    “The replacement albumin is >95% pure by manufacturer’s analysis”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductnone given

    After background subtraction, total protein intensities were normalized to negative control as fold-increments with a cut-off of 2 folds as significant increase, and then normalized to positive control to compare across samples in respective groups.

    “After background subtraction, total intensities for each protein were normalized to negative control as fold-increments with a cut-off of 2 folds as significant increase. Finally, respective intensities were normalized to positive control to compare against different samples in respective groups.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductown data

    BrdU-positive cells were counted and estimated by two blinded researchers, with the results averaged.

    “Samples were immunostained for BrdU using acid antigen retrieval and % BrdU+ve cells were counted and estimated by two blinded researchers, with the results averaged.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    IL-8 receptor signaling promotes cell survival, migration, chemotaxis, angiogenesis, and oligodendrocyte positioning, and might attenuate neuropathy.

    “IL-8 receptor signaling promotes cell survival, migration, chemotaxis, angiogenesis, oligodendrocyte positioning, and might attenuate neuropathy [72].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Li, 2020, The therapeutic potential of chemokines in the treatment of chemotherapy- induced peripheral neuropathy., Curr Drug Targets source

  • Probably not a substantial claim.

    Premisecitation

    MIP2 controls migration of neutrophils to sites of inflammation.

    “MIP2 controls migration of neutrophils to sites of inflammation”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Beuscher, 2001, Constitutive expression of macrophage-inflammatory protein 2 (MIP-2) mRNA in bone marrow gives rise to peripheral neutrophils with preformed MIP-2 protein., J Immunol source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    Multiple mechanisms may contribute to the rejuvenation of the three germ layer tissues by NBE, with the described model being just one.

    “It is also quite possible that multiple mechanisms contribute to the rejuvenation of the three germ layer tissues by NBE, with the above described model being just one.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    CSF albumin is a marker of brain aging and disease.

    “and CSF albumin is a marker of brain aging and disease.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    PF4 promotes platelet aggregation, is broadly chemotactic, plays a role in wound repair, and has anti-microbial activity.

    “PF4 promotes platelet aggregation, it is broadly chemotactic, plays a role in wound repair and has anti-microbial activity [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Bender, 2019, Rho GTPases and their downstream effectors in megakaryocyte biology., Platelets source

  • It may state two separate claims as one.

    Interpretationcitation

    An increase of angiogenic regulators is expected to broadly contribute to improved vascularization and, through increased tissue perfusion, to tissue repair.

    “an increase of angiogenic regulators is expected to broadly contribute to improved vascularization [73, 74] and through this increased perfusion of tissues, to tissue repair.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [73] Klagsbrun, 1987, Angiogenic factors., Science source
    • cites [74] Risau, 1990, Angiogenic growth factors., Prog Growth Factor Res source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Follistatin-like has broad anti-inflammatory properties and is expected to promote better health broadly in a mammal.

    “And, follistatin-like has broad anti-inflammatory properties [80], which are also expected to promote better health broadly in a mammal.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Hirsch, 2014, Follistatin-like protein 1 and its role in inflammation and inflammatory diseases., Immunol Res source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    All in vivo experiments and procedures were performed in accordance with the policies set by the Office of Laboratory Animal Care and under the approved protocol.

    “All in vivo experiments and procedures were performed in accordance with the policies set by the Office of Laboratory Animal Care and under the approved protocol.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductown data

    Human blood samples were provided under an IRB approved by Sutter Health, without personal identifiers, and were not linked to or traced back to personal information.

    “On shelf samples of human blood (collected through the FDA approved and routinely used in the clinic procedure of Therapeutic Plasma Exchange [16–18]) were provided to us by Dr. Dobri Kiprov (IRB Approved by Sutter health, 648823) without personal identifiers and were not linked to or traced back to any personal information in our study.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Kiprov, 2003, Therapeutic apheresis delivery systems in the US., Transfus Apher Sci source
    • cites [17] Hunnicutt, 2001, Adverse reactions associated with mobile therapeutic apheresis: analysis of 17,940 procedures., J Clin Apher source
    • cites [18] Hofmann, 2003, Plasmapheresis in immunologically mediated polyneuropathies., Ther Apher Dial source

  • It may state two separate claims as one.

    Interpretationreasoning

    Albumin is not the only determinant of NBE/TPE, but it might contribute particularly when age-elevated factors become diluted.

    “Overall, it does not seem that albumin is the only determinant of NBE/TPE, but it might have a contribution particularly when the age-elevated factors become diluted.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Changes in every autoinductive protein, secondary target, and receptor are not expected to be simultaneously detected at any given time point, but many are observed at 6 days post NBE and 1 month after TPE.

    “changes in every autoinductive protein, secondary target, receptor, etc. are not expected to be simultaneously detected at any given time point, but many are indeed observed at 6 days post NBE and 1 month after TPE.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: In the Figure 6 model, protein A induces itself and C, A represses B, and C represses A.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationnone given

    The study does not exclude the possibility that young blood factors, sharing of young organs, and environmental enrichment might also contribute to the rejuvenative effects of heterochronic parabiosis.

    “This study does not exclude the possibility that factors that are present in young blood, as well as sharing of young organs and environmental enrichment, might also contribute to the rejuvenative effects of heterochronic parabiosis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    One outlier with very low cell numbers, one well out of six for one sample, was removed from the data analysis.

    “One outlier with very low cell numbers, e.g. one well (out of 6) for one sample was removed from the data analysis.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Better overall organ health and repair and better success of vaccination are predicted.

    “hence better overall organ health and repair, better success of vaccination is predicted.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationreasoning

    Many observed molecular systemic changes may be simultaneously required for enhancement of maintenance and health of old tissues, or smaller groups of these proteins might suffice for multi-tissue or tissue-specific rejuvenation.

    “It is possible that many of the observed molecular systemic changes are simultaneously required for the enhancement of maintenance and health of old tissues, or alternatively, smaller groups of these proteins might suffice for multi-tissue or tissue-specific rejuvenation.”
    Quote in the paperNot a substantial claim
60 of 60

  • The paper relies on this without support.

    The NBE procedure, replacing half of the plasma with saline containing 5% albumin, is a neutral age blood exchange that does not itself introduce rejuvenative factors beyond dilution of plasma factors and albumin replenishment.

    “terming it a “neutral” age blood exchange, NBE”
    “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 (e.g. replenishing the depletion of blood albumin).”

  • The authors state this as an assumption.

    In the Figure 6 model, protein A induces itself and C, A represses B, and C represses A.

    “System: A induces itself (A, red), and C (blue); A represses B (green), C represses A.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Simple dilution of the blood of old mice with saline buffer containing 5% albumin induces rejuvenation in multiple tissues.

    “and the simple dilution of the blood of old mice with saline buffer containing 5% albumin induces rejuvenation in multiple tissues 230 ,”

    From Hallmarks of aging: An expanding universe (2023) · cites this paper as [230]

  • In mice, dilution of blood from old mice with saline/albumin caused rejuvenation in multiple tissues.

    “| | Mouse | Dilution of blood from old mice with saline/ albumin | Rejuvenation in multiple tissues | 230”

    From Hallmarks of aging: An expanding universe (2023) · cites this paper as [230]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Liver fibrosis index is defined as both a count and an area fraction

    Major

    Figure 4 defines the fibrotic index as the number of clusters per section, but the methods say cluster areas were divided by total liver-tissue area. These are different measurements.

  • Human proteomics array is reported as both 507 and 506 proteins

    Minor

    The Figure 5 caption reports a 507-protein human array, whereas the methods report a 506-protein array for the human serum measurements.

2 of 2

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Metadata

Authors
Mehdipour, M., Skinner, C., Wong, N., Lieb, M., Liu, C., Etienne, J., Kato, C., Kiprov, D., Conboy, M. J., & Conboy, I. M.
Affiliations
  • University of California, Berkeley (US)
  • California Pacific Medical Center (US)
Corresponding author
Conboy, Irina M.
ORCID
Venue
Aging
Publisher
Impact Journals, LLC
Published
2020-05-30
Volume
12
Issue
10
Pages
8790-8819
ISSN
1945-4589 (ISSN-L)
DOI
10.18632/aging.103418
PMC
PMC7288913
OpenAlex
W3029504057
Cited by
115
References
86
Citations by year
2026: 19 · 2025: 17 · 2024: 19 · 2023: 21 · 2022: 18 · 2021: 15 · 2020: 6
FWCI
4.85
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Aging (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • Open Philanthropy Project
  • National Institutes of Health (NIH T32, NIH R56)
  • National Institute on Aging (R56AG058819)
  • National Heart, Lung, and Blood Institute (R01HL139605)
  • National Institute of Biomedical Imaging and Bioengineering (R01EB023776)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
plasma exchange, albumin, serum proteomics, muscle repair, liver fibrosis, hippocampal neurogenesis, progenitor cell proliferation, systemic signaling
MeSH terms
Saline Solution, Aging, Albumins, Animals, Cells, Cultured, Germ Layers, Humans, Male, Mice, Inbred C57BL, Plasma, Plasma Exchange, Rejuvenation, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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