The DOI matches its Crossref record; 86 of the 86 references it cites were found in a registry or an index; 8 of the 70 sources its claims cite were checked for support.
Asynchronous, contagious and digital aging
Open accessAbstract
Aging has largely been defined by analog measures of organ and organismal dysfunction. This has led to the characterization of aging processes at the molecular and cellular levels that underlie these gradual changes. However, current knowledge does not fully explain the growing body of data emerging from large epidemiological, systems biology, and single cell studies of entire organisms pointing to varied rates of aging between individuals (different functionality and lifespan), across lifespan (asynchronous aging), and within an organism at the tissue and organ levels (aging mosaicism). Here we consider these inhomogeneities in the broader context of the rate of aging and from the perspective of underlying cellular changes. These changes reflect genetic, environmental, and stochastic factors that cells integrate to adopt new homeostatic, albeit less functional, states, such as cellular senescence. In this sense, cellular aging can be viewed, at least in part, as a quantal process we refer to as "digital aging". Nevertheless, analog declines of tissue dysfunction and organ failure with age could be the sum of underlying digital events. Importantly, cellular aging, digital or otherwise, is not uniform across time or space within the organism or between organisms of the same species. Certain tissues may exhibit earliest signs of cellular aging, acting as drivers for organismal aging as signals from those driver cells within those tissues may accelerate the aging of other cells locally or even systemically. Advanced methodologies at the systems level and at the single cell level are likely to continue to refine our understanding to the processes of how cells and tissues age and how the integration of those processes leads to the complexities of individual, organismal aging.
Overview
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TL;DR
This Perspective argues that aging is asynchronous across individuals, across the lifespan, and among tissues, with discrete cellular state transitions (“digital aging”) and local/systemic spread (“contagious aging”) contributing to organismal decline. It calls for biomarkers and single-cell/systems approaches to measure rates of aging rather than relying on lifespan alone.
Key findings
- Aging is non-uniform over time: cited studies report non-linear trajectories, including DNA methylation changing 24 times faster in the first few years of life than after puberty, inflection points around ages 70 and 85 in an 845-person Swedish cohort, two rapid epigenomic-change peaks around ages 40 and 60–70 in peripheral blood mononuclear cells, four “phases of aging” in skin from 121 humans aged 21–76, and brain-connectivity transitions around ages 40 and 70–75.
- Aging is non-uniform across tissues and individuals: transcriptomic changes in 17 mouse organs across 10 ages show different trajectories; a human multi-omics study suggested different individuals manifest different “ageotypes”; single-cell studies show mosaicism, and in old versus young mice the proportion of cells expressing the senescence marker p16 more than doubled in multiple tissues.
- Cellular aging can be viewed partly as “digital” or quantal: cell death and cellular senescence are discrete states, and analog tissue decline may be the sum of underlying digital events; senescent-cell secretome can induce senescence in neighboring cells.
- Aging may be “contagious” locally and systemically: parabiosis and plasma-infusion studies show blood-borne factors can promote or reverse aging phenotypes, with aged plasma accelerating and young plasma reversing brain endothelial cell transcriptome aging; chronic diseases such as cancer, diabetes, and HIV/AIDS are linked to later co-morbidities, consistent with “aging begets aging.”
Methods
- Design: Perspective/review article; no new experiments, primary data, or formal meta-analysis reported.
- Evidence base: synthesizes cited epidemiological, omics, single-cell, parabiosis, and plasma-infusion studies across model organisms and humans.
- Analysis: conceptual synthesis proposing “asynchronous,” “digital,” and “contagious” aging frameworks; no statistical methods or systematic search strategy are described.
Limitations
- Stated: No unified theory of the molecular basis of cellular aging has emerged; the authors explicitly do not attempt to define aging, its causes, or when underlying changes begin, and identifying non-genetic/non-environmental determinants of individual aging rates remains a major challenge.
- Stated: The relative contribution of analog versus digital cellular aging as drivers of tissue aging, and whether lifespan/healthspan interventions shift digital states, remain to be determined by further single-cell studies.
- Evident: As a Perspective, it presents a selective conceptual synthesis rather than a systematic review or primary analysis; many cited examples come from model organisms, limiting direct generalizability to humans.
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Claims the paper makes
46 Not checked yet · 37 Own interpretation · 3 Partly supported · 1 Supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In humans, a meta-analysis of >300 brains and 17 brain regions showed broad non-linear changes in gene expression which varied across brain regions with age.33”
§ Asynchronous, contagious and digital aging > Variations in the rate of aging in an individual across time and space
What the sources say
- Partly supportedcites [33] Isildak, U., Somel, M., Thornton, J. M. & Donertas, H. M. Temporal changes in the gene expression heterogeneity during brain development and aging. Sci. Rep. 10, 4080 (2020). sourceExperimental — accuracy not yet measured
The Results describe a meta-analysis using samples from 17 brain regions, but those samples came from 298 individuals, not more than 300. The paper examines age-related gene-expression changes, including different trajectories during development and aging; however, its Discussion says the meta-analysis focused on patterns consistent across datasets and could not capture patterns specific to individual brain regions. The quoted claim therefore overstates both the participant count and what this analysis showed about regional variation. (LLM, conf=0.88)
plaincorrelationaln = 300- Asserted: passes — The authors put it forward as true.
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In Drosophila, dysfunction of the gut and skeletal muscle appear to be primary drivers of aging and mortality.39,40,41,42”
§ Asynchronous, contagious and digital aging > Variations in the rate of aging in an individual across time and space
What the sources say
- Partly supportedcites [39] Biteau, B., Hochmuth, C. E. & Jasper, H. JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell 3, 442–455 (2008). sourceExperimental — accuracy not yet measured
The Discussion section “Age-related changes in the intestinal epithelium” reports loss of gut tissue homeostasis in aging flies, supporting the gut-dysfunction portion. It does not establish gut dysfunction as a primary driver of aging or mortality, and our copy does not address skeletal-muscle dysfunction in that role (searched: skeletal muscle, mortality, lifespan). (LLM, conf=0.86)
- Partly supportedcites [40] Clark, R. I. et al. Distinct shifts in microbiota composition during Drosophila aging impair intestinal function and drive mortality. Cell Rep. 12, 1656–1667 (2015). sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) links age-related intestinal decline in Drosophila to reduced lifespan and reports that a microbiota shift following intestinal barrier failure is a primary cause of death. It does not address skeletal muscle dysfunction as a driver of aging or mortality, so it supports only the gut portion of the claim. (LLM, conf=0.87)
- Partly supportedcites [41] Demontis, F. & Perrimon, N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell 143, 813–825 (2010). sourceExperimental — accuracy not yet measured
The Discussion reports that reducing muscle aging extends lifespan in Drosophila and proposes that muscle aging may be a key determinant of systemic aging. It does not establish gut dysfunction as a driver of aging or mortality, so it supports the muscle portion of the sentence but not the whole claim. (LLM, conf=0.86)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Pharmacologic and dietary interventions that extend lifespan in model organisms and may do so by slowing aging rates are increasingly being developed for testing in humans.75”
§ Asynchronous, contagious and digital aging > Aging and disease: Chicken and egg?
What the sources say
- Supportedcites [75] Longo, V. D. et al. Interventions to slow aging in humans: are we ready? Aging Cell 14, 497–510 (2015). source
The Abstract says dietary and pharmacologic approaches have emerged and identifies strategies selected for testing in humans, based partly on pro-longevity evidence in model organisms and rodents. The Introduction also says such interventions have been identified and calls for cautious human testing. (LLM, conf=0.92)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These findings, as well as many follow up studies,66,67,68 including the demonstration that plasma infusions alone are sufficient to exert these effects,65,69 have unequivocally demonstrated that factors in the blood are able to communicate information from one or more source tissues to other tissues throughout the body.”
§ Asynchronous, contagious and digital aging > Is aging contagious?
What the sources say
- Partly supportedcites [66] Ruckh, J. M. et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10, 96–103 (2012). sourceExperimental — accuracy not yet measured
The Results report that spinal cord lesions in old mice were exposed to circulating cells and soluble factors from a young parabiotic partner; the Discussion says circulating factors can partly reverse age-related deficiencies in CNS repair. This supports blood-borne effects across individuals, but the study does not establish communication from source tissues to other tissues throughout the body. (LLM, conf=0.83)
- Supportedcites [67] Salpeter, S. J. et al. Systemic regulation of the age-related decline of pancreatic β-cell replication. Diabetes 62, 2843–2848 (2013). source
The Discussion reports that exposure to a young circulation increased β-cell replication in old mice, and that transplanting islets between young and old mice changed their replication rates. It also describes similar systemic effects in other organs. These passages support the attributed point that circulating factors can convey effects between tissues; the sentence cites other studies for the separate plasma-infusion claim. (LLM, conf=0.88)
- Supportedcites [68] Katsimpardi, L. et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630–634 (2014). source
The Abstract reports that factors found in young blood affect the aging mouse brain, inducing vascular remodeling and increased neurogenesis. The paper also describes circulating factors as systemic regulators, supporting the attributed point that blood-borne factors can act on tissues elsewhere in the body. The plasma-infusion clause is attached to other citations, not this source. (LLM, conf=0.87)
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Evidence in C. elegans has provided support for this idea by demonstrating that genetic interventions that extend lifespan may do so without comparably altering the relevant aging phenotypes.17”
§ Asynchronous, contagious and digital aging > Lifespan versus aging
What the sources say
- Not checked yetcites [17] Bansal, A., Zhu, L. J., Yen, K. & Tissenbaum, H. A. Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants. Proc. Natl Acad. Sci. USA 112, E277–E286 (2015). source
boostedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“as there are almost no aspects of anatomy or physiology that do not exhibit declines as an individual ages.23”
§ Asynchronous, contagious and digital aging > Rates of aging
What the sources say
- Not checked yetcites [23] Khan, S. S., Singer, B. D. & Vaughan, D. E. Molecular and physiological manifestations and measurement of aging in humans. Aging Cell 16, 624–633 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, even for genetically identical organisms maintained in identical environments, there remains a large variability of aging trajectories (presumably related to different rates of aging) as determined by lifespan.22”
§ Asynchronous, contagious and digital aging > Rates of aging
What the sources say
- Not checked yetcites [22] Kirkwood, T. B. et al. What accounts for the wide variation in life span of genetically identical organisms reared in a constant environment? Mech. Ageing Dev. 126, 439–443 (2005). source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nevertheless, analog declines of tissue dysfunction and organ failure with age could be the sum of underlying digital events.”
§ Asynchronous, contagious and digital aging > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“While lifespan is a measure that incorporates the impacts of aging, the determinants of longevity are distinct from those that influence the rate at which an organism ages.14”
§ Asynchronous, contagious and digital aging > Lifespan versus aging
What the sources say
- Not checked yetcites [14] Hayflick, L. Entropy explains aging, genetic determinism explains longevity, and undefined terminology explains misunderstanding both. PLoS Genet. 3, e220 (2007). source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, cellular aging, digital or otherwise, is not uniform across time or space within the organism or between organisms of the same species.”
§ Asynchronous, contagious and digital aging > Abstract
plain- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 14
- It may state two separate claims as one. 10
In the paper
“In general, the decline of tissue function is commonly illustrated as gradual and steady,23 perhaps with a more rapid decline toward the end of life.”
§ Asynchronous, contagious and digital aging > Variations in the rate of aging in an individual across time and space
What the sources say
- Not checked yetcites [23] Khan, S. S., Singer, B. D. & Vaughan, D. E. Molecular and physiological manifestations and measurement of aging in humans. Aging Cell 16, 624–633 (2017). source
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Ultrastructural studies in C. elegans almost two decades ago hinted that it might not.30 The authors noted not only vastly different rates of aging of tissues and cells in individual worms, which they ascribed largely to stochastic events, but the onset of degenerative changes was neither linear nor synchronized.”
§ Asynchronous, contagious and digital aging > Variations in the rate of aging in an individual across time and space
What the sources say
- Not checked yetcites [30] Herndon, L. A. et al. Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 419, 808–814 (2002). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this sense, cellular aging can be viewed, at least in part, as a quantal process we refer to as “digital aging”.”
§ Asynchronous, contagious and digital aging > Abstract
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Within any tissue, changes in the cellular composition could be a result of changes in proportions of resident cells (such as, for example, an increase in the proportion of fibroblasts or resident macrophages) or to intrinsic changes to subpopulations without any change in cellular proportions.”
§ Asynchronous, contagious and digital aging > Variations in the rate of aging in an individual across time and space
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“In a groundbreaking single cell study, RNA isolated from individual cardiomyocytes of young and old mice showed broad mosaicism in gene expression among cells within individual mice and increased differences in expression between cells.45.”
§ Asynchronous, contagious and digital aging > Variations in the rate of aging in an individual across time and space
What the sources say
- Not checked yetcites [45] Bahar, R. et al. Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 441, 1011–1014 (2006). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, spatially, there is clear heterogeneity of aging rates among tissues, and the aging of members of one species may be driven by functional loss of tissues that are different from those in another species.”
§ Asynchronous, contagious and digital aging > Variations in the rate of aging in an individual across time and space
boostedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Nevertheless, such cellular states are routinely determined as discrete and quantal rather than continuous.”
§ Asynchronous, contagious and digital aging > Digital aging versus analog aging
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The death of a cell can be considered one such digital readout – cells are either alive or dead.”
§ Asynchronous, contagious and digital aging > Digital aging versus analog aging
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Aging is associated with changes in the population of immune cells infiltrates,51 and caloric restriction can reverse those trends.50”
§ Asynchronous, contagious and digital aging > Digital aging versus analog aging
What the sources say
- Not checked yetcites [51] Kimmel, J. C. et al. Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging. Genome Res. 29, 2088–2103 (2019). source
- Not checked yetcites [50] Ma, S. et al. Caloric restriction reprograms the single-cell transcriptional landscape of Rattus norvegicus aging. Cell 180, 984–1001 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This notion of aging by quantal steps can clearly be extended to the subcellular world to explore proximal causes of age-related changes in cellular phenotypes.”
§ Asynchronous, contagious and digital aging > Digital aging versus analog aging
boosted- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“With this model taken to its extreme, the analog decline of the function of a tissue can be modeled as a result of the gradual accumulation of cells that have transitioned from a functional to one or more dysfunctional states.”
§ Asynchronous, contagious and digital aging > Digital aging versus analog aging
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In the paper
“However, at the cellular level, the possibility of a certain amount “digital aging” needs also to be considered, digital in the sense of discrimination by discrete units, not necessarily binary units (Figure 3).”
§ Asynchronous, contagious and digital aging > Digital aging versus analog aging
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“These observations are supported by a rapidly growing number of single cell RNA sequencing studies showing greater cell-to-cell variability in gene expression in human T cells and pancreatic cells, as well as differences in cellular mutation rates with age.47,48”
§ Asynchronous, contagious and digital aging > Variations in the rate of aging in an individual across time and space
What the sources say
- Not checked yetcites [47] Martinez-Jimenez, C. P. et al. Aging increases cell-to-cell transcriptional variability upon immune stimulation. Science 355, 1433–1436 (2017). source
- Not checked yetcites [48] Enge, M. et al. Single-cell analysis of human pancreas reveals transcriptional signatures of aging and somatic mutation patterns. Cell 171, 321–330 (2017). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The extent to which cellular aging is due to digital versus analog changes at the molecular level is certain to depend of which cellular phenotype is under consideration in the same way that different tissues may exhibit age-related changes as a result of digital cellular aging to different degrees.”
§ Asynchronous, contagious and digital aging > Digital aging versus analog aging
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Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“None of these transitions occurs instantaneously, and there are clearly intermediate states.”
§ Asynchronous, contagious and digital aging > Digital aging versus analog aging
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In the paper
“Cells of the same type have vastly different ages based on DNA dating (including postmitotic cells), some as old as the animal, and subcellular structures within individual neurons or pancreatic beta cells have different ages based on protein dating.”
§ Asynchronous, contagious and digital aging > Variations in the rate of aging in an individual across time and space
What the sources say
- Not checked yetcites [46] Arrojo e Drigo, R. et al. Age mosaicism across multiple scales in adult tissues. Cell Metab. 30, 343–351 (2019). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Likewise, cellular senescence is another digital cellular state in the sense that cells can be classified by various markers as being either senescent or non-senescent.54”
§ Asynchronous, contagious and digital aging > Digital aging versus analog aging
What the sources say
- Not checked yetcites [54] Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Indeed, single cell RNAseq studies of brain endothelial cell aging showed that infusion of aged plasma can accelerate while young plasma can reverse aging as a function of the transcriptome.70”
§ Asynchronous, contagious and digital aging > Is aging contagious?
What the sources say
- Not checked yetcites [70] Chen, M. B. et al. Brain endothelial cells are exquisite sensors of age-related circulatory cues. Cell Rep. 30, 4418–4432 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“It has long been known that the major risk factor for the vast majority of chronic diseases is age itself.71”
§ Asynchronous, contagious and digital aging > Aging and disease: Chicken and egg?
What the sources say
- Not checked yetcites [71] Niccoli, T. & Partridge, L. Ageing as a risk factor for disease. Curr. Biol. 22, R741–R752 (2012). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A more thorough understanding of the molecular processes of aging, the cellular basis of tissue aging, and the local and systemic communication networks that can accelerate or decelerate the rate of aging will certainly increase the number and diversity interventions to extend healthspan.”
§ Asynchronous, contagious and digital aging > Aging and disease: Chicken and egg?
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Such a model provides a framework for incorporating findings that highlight phenotypes of aging that deviate from models of uniform and synchronized processes throughout an organism.”
§ Asynchronous, contagious and digital aging > Conclusion
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“If successful, this would not only slow the structural and functional declines that are the quintessential features of the organismal aging, but also would reduce the incidence of age-related diseases.”
§ Asynchronous, contagious and digital aging > Aging and disease: Chicken and egg?
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As the number of distinct measures and biomarkers of aging increases and as the technologies to quantify them develop, the picture that emerges of the patterns of aging will continue to become increasingly more complex.”
§ Asynchronous, contagious and digital aging > Conclusion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Coupled with technological advances to measure aging phenotypes and rates of aging at the cellular, tissue, and organismal levels, this will also likely increase the pace of the translation from the laboratory to the clinic.”
§ Asynchronous, contagious and digital aging > Aging and disease: Chicken and egg?
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper relies on this without support.
Aging has largely been defined by analog measures of organ and organismal dysfunction.
“Aging has largely been defined by analog measures of organ and organismal dysfunction.”
The paper relies on this without support.
Current knowledge does not fully explain the growing body of data emerging from large epidemiological, systems biology, and single cell studies of entire organisms pointing to varied rates of aging between individuals, across lifespan, and within an organism at the tissue and organ levels.
“However, current knowledge does not fully explain the growing body of data emerging from large epidemiological, systems biology, and single cell studies of entire organisms pointing to varied rates of aging between individuals (different functionality and lifespan), across lifespan (asynchronous aging), and within an organism at the tissue and organ levels (aging mosaicism).”
The paper relies on this without support.
Within any given species, there will be individuals that age more rapidly and those that age more slowly.
“Within any given species, there will be individuals that age more rapidly and those that age more slowly.”
The authors state this as an assumption.
Nearly all animals in a protected environment will age before dying.
“Assuming that nearly all animals in a protected environment will age before dying, it is almost tautological that members of a species whose maximal lifespan is 100 days age more rapidly than those from a species whose maximal lifespan is 100 years.”
The paper relies on this without support.
Identifying which factors determine individual rates of aging remains a major challenge to the field.
“Identifying which factors (especially if not genetic and not environmental) determine individual rates of aging remains a major challenge to the field.”
The paper relies on this without support.
In many diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, intracellular aggregation of proteins is a cardinal feature of the pathology.
“In many diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, a cardinal feature of the pathology is intracellular aggregation of proteins.”
The paper relies on this without support.
Some prions are truly contagious, in the sense of being transmissible between individuals or across species.
“Of course, some prions are truly contagious, in the sense of being transmissible between individuals or across species”
The paper relies on this without support.
Protein aggregation can be self-propagating.
“since protein aggregation can be self-propagating”
The paper relies on this without support.
Protein aggregation is one of the key features of cellular aging.
“As protein aggregation is one of the key features of cellular aging”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In aging tissues, molecular and cellular changes disrupt spatial organization, resulting in uneven functional decline.”
From Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging (2024) · cites this paper as [6]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“However, as tissues age at different rates41,42,75,76, there is likely a limit to how well ageing of blood cells can measure and explain mechanisms of ageing of the rest of the body; perhaps this is evidenced by the small (albeit statistically significant) associations between second-generation ageing clocks and organ-specific measures of age-related dysfunction.”
From Measuring biological age using omics data (2022) · cites this paper as [75]
In the citing paper
“Ageing is characterized by a decline in all organ function and a striking increase in multi-organ diseases1.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [1]
Citations
Cites
DNA methylation age of human tissues and cell types
Horvath, S. (2013) · Genome Biology · doi:10.1186/gb-2013-14-10-r115 · Cited by 7,075
Pleiotropy, natural selection, and the evolution of senescence.
Williams, G. C. (1957) · Evolution · doi:10.1111/j.1558-5646.1957.tb02911.x · Cited by 4,279
Cellular Senescence: Defining a Path Forward
Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.005 · Cited by 3,225
Nothing in Biology Makes Sense except in the Light of Evolution
Dobzhansky, T. (1973) · The American Biology Teacher · doi:10.2307/4444260 · Cited by 3,219
Extending Healthy Life Span—From Yeast to Humans
Fontana, L., Partridge, L., & Longo, V. D. (2010) · Science · doi:10.1126/science.1172539 · Cited by 3,023
Geroscience: Linking Aging to Chronic Disease
Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., Franceschi, C., Lithgow, G. J., Morimoto, R. I., Pessin, J. E., et al. (2014) · Cell · doi:10.1016/j.cell.2014.10.039 · Cited by 2,764
Self-citationRejuvenation of aged progenitor cells by exposure to a young systemic environment
Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. A. (2005) · Nature · doi:10.1038/nature03260 · Cited by 2,287
Self-citationA complex secretory program orchestrated by the inflammasome controls paracrine senescence
Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2784 · Cited by 2,278
Kirkwood, T. B. L. (1977) · Nature · doi:10.1038/270301a0 · Cited by 2,007
Ageing as a Risk Factor for Disease
Niccoli, T., & Partridge, L. (2012) · Current Biology · doi:10.1016/j.cub.2012.07.024 · Cited by 1,831
Research works printed but not linked: 1
- Pearl, R. The Rate of Living (University of London Press, 1928).
Cited by
Sorted by citations
Measuring biological age using omics data
Rutledge, J., Oh, H., & Wyss-Coray, T. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-022-00511-7 · Cited by 570
Self-citationCai, Y., Song, W., Li, J., Jing, Y., Liang, C., Zhang, L., Zhang, X., Zhang, W., Liu, B., An, Y., et al. (2022) · Science China Life Sciences · doi:10.1007/s11427-022-2161-3 · Cited by 450
Ageing and rejuvenation of tissue stem cells and their niches
Brunet, A., Goodell, M. A., & Rando, T. A. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00510-w · Cited by 407
Self-citationMaking sense of the ageing methylome
Seale, K., Horvath, S., Teschendorff, A., Eynon, N., & Voisin, S. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-022-00477-6 · Cited by 274
Metformin decelerates aging clock in male monkeys
Yang, Y., Lu, X., Liu, N., Ma, S., Zhang, H., Zhang, Z., Yang, K., Jiang, M., Zheng, Z., Qiao, Y., et al. (2024) · Cell · doi:10.1016/j.cell.2024.08.021 · Cited by 227
Metadata
- Authors
- Rando, T. A., & Wyss-Coray, T.
- Affiliations
- VA Palo Alto Health Care System (US)
- Corresponding author
- Rando, Thomas A.
- Venue
- Nature Aging
- Published
- 2021-01-14
- Volume
- 1
- Issue
- 1
- Pages
- 29-35
- ISSN
- 2662-8465 (ISSN-L)
- PMC
- PMC8248898
- OpenAlex
- W3119607554
- Cited by
- 121
- References
- 86
- Citations by year
- 2026: 20 · 2025: 21 · 2024: 24 · 2023: 19 · 2022: 29 · 2021: 8
- FWCI
- 7.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NOMIS Stiftung (n/a)
- Nan Fung Life Sciences
- The Glenn Foundation for Medical Research
- 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 › Single-cell and spatial transcriptomics
- Keywords
- digital aging, cellular senescence, cellular aging, aging rate, tissue-specific aging, organ dysfunction, lifespan variation, stochastic aging
- MeSH terms
- Aging, Humans, Longevity, Cellular Senescence
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 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (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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