Asynchronous, contagious and digital aging

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”

What the sources say

• Partly supported

  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)

  cites [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

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”

What the sources say

• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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

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”

What the sources say

• Supported

  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)

  cites [75] Longo, V. D. et al. Interventions to slow aging in humans: are we ready? Aging Cell 14, 497–510 (2015). source

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.”

What the sources say

• Partly supported

  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)

  cites [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
• Supported

  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)

  cites [67] Salpeter, S. J. et al. Systemic regulation of the age-related decline of pancreatic β-cell replication. Diabetes 62, 2843–2848 (2013). source
• Supported

  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)

  cites [68] Katsimpardi, L. et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630–634 (2014). source

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”

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

In the paper

“as there are almost no aspects of anatomy or physiology that do not exhibit declines as an individual ages.23”

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

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”

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

In the paper

“Nevertheless, analog declines of tissue dysfunction and organ failure with age could be the sum of underlying digital events.”

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”

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

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.”

In the paper

“Therefore, it is possible for measured lifespan to be uncoupled, at least to a large extent, from the consequences of aging – recording of the death of a person provides no information as to how functional that person was over the previous decades.”

What the sources say

• Not checked yetcites [16] Brett, J. O. & Rando, T. A. Alive and well? Exploring disease by studying lifespan. Curr. Opin. Genet. Dev. 26, 33–40 (2014). source

In the paper

“At the level of an individual, a rate of aging can be determined by the rate of change of virtually any anatomic structure or physiological process (e.g., bone density, renal function, etc., for humans), as there are almost no aspects of anatomy or physiology that do not exhibit declines as an individual ages.23”

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

In the paper

“This point highlights a second key aspect of measurements of rates of change of biomarkers, and that is that the accuracy of the rate, and especially changes in rate, will increase as the number of longitudinal measurements increase.”

In the paper

“In addition, tissues within human and mouse individuals show unique DNA methylation rates.34,25.”

What the sources say

• Not checked yetcites [34] Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013). source
• Not checked yetcites [25] Stubbs, T. M. et al. Multi-tissue DNA methylation age predictor in mouse. Genome Biol. 18, 68 (2017). source

In the paper

“A recent study of some 3,000 proteins in blood of over 4,000 healthy people concluded that markers of aging do not in fact suggest at monotonic aging process, but instead show periods of accelerated change and periods of slower change.28”

What the sources say

• Not checked yetcites [28] Lehallier, B. et al. Undulating changes in human plasma proteome profiles across the lifespan. Nat. Med. 25, 1843–1850 (2019). source

In the paper

“In addition to these variations in rates of organismal aging over time, the above studies also provide clear evidence for the lack of uniformity of underlying aging process across space, namely among tissues in an individual (Figure 2).”

In the paper

“Inflection points in DNA methylation indicative of non-monotonous changes were also observed in a 20-year follow-up Swedish aging cohort of 845 individuals around ages 70 and 85.35”

What the sources say

• Not checked yetcites [35] Li, X. et al. Longitudinal trajectories, correlations and mortality associations of nine biological ages across 20-years follow-up. eLife 9, e51507 (2020). source

In the paper

“Similarly, DNA methylation, which shows a remarkable correlation with aging across species, was reported to be 24 times faster during the first few years of life compared to after puberty.34”

What the sources say

• Not checked yetcites [34] Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013). source

In the paper

“Interestingly, functional MRI measurements of brain connectivity seem to support these asynchronous molecular measurements, showing non-linear changes and transition points around ages 40 and 70–75 years of age.38”

What the sources say

• Not checked yetcites [38] Edde, M., Leroux, G., Altena, E. & Chanraud, S. Functional brain connectivity changes across the human life span: from fetal development to old age. J. Neurosci. Res. 99, 236–262 (2020). source

In the paper

“Undoubtedly, for any given species, there are certain tissues and organs whose functions decline earliest and most rapidly.”

In the paper

“Peripheral blood mononuclear cells exhibit two distinct peaks of rapid epigenomic changes in humans, one around 40 years of age and another around 60–70 years of age.36”

What the sources say

• Not checked yetcites [36] Marquez, E. J. et al. Sexual-dimorphism in human immune system aging. Nat. Commun. 11, 751 (2020). source

In the paper

“Likewise, a longitudinal study of the transcriptome and DNA methylation state of skin in 121 humans between 21 and 76 years of age revealed 4 distinct “phases of aging” highlighted by the activity of different biological processes.37”

What the sources say

• Not checked yetcites [37] Holzscheck, N. et al. Multi-omics network analysis reveals distinct stages in the human aging progression in epidermal tissue. Aging 12, 12393–12409 (2020). source

In the paper

“For example, in humans the cardiovascular system exhibits a much greater functional decline with age than the gastrointestinal system,23 at least based on physiological parameters measured, as noted above, on absolute scales.”

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

In the paper

“Analysis of bulk populations of cells may fail to reveal such a distinction, but single cell analysis has the potential to reveal the relative contribution of these two distinct, but of course not mutually exclusive, processes of tissue aging.”

In the paper

“Mathematical modeling of longevity curves in flies also suggest at least 2 phases of aging with a sharp transition in between states characterized by intestinal degeneration.31”

What the sources say

• Not checked yetcites [31] Tricoire, H. & Rera, M. A new, discontinuous 2 phases of aging model: lessons from Drosophila melanogaster. PLoS ONE 10, e0141920 (2015). source

In the paper

“Isotope-based dating of DNA and protein at the ultrastructural level in various tissues in mice revealed extensive cellular mosaicism within aging tissues.46”

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

In the paper

“Therefore, for any given species, although there may be certain organs and tissues that tend to be the most susceptible to functional decline with age, which is the actual driver of organismal aging for any given member of that species is highly variable.”

In the paper

“Transcriptional changes in 17 organs across 10 ages from neonatal to 30-month-old-mice show very different trajectories of aging with varied onset and amplitudes of changes.32”

What the sources say

• Not checked yetcites [32] Schaum, N. et al. Ageing hallmarks exhibit organ-specific temporal signatures. Nature 583, 596–602 (2020). source

In the paper

“In one pioneering human study, a multi-omics analysis of aging biomarkers suggested that different individuals manifest different “ageotypes”, meaning that the tissue that ages most rapidly differs from one person to another.44”

What the sources say

• Not checked yetcites [44] Ahadi, S. et al. Personal aging markers and ageotypes revealed by deep longitudinal profiling. Nat. Med. 26, 83–90 (2020). source

In the paper

“As mentioned above, transcriptomic studies strongly agree that tissues, organs, and even sub-regions within an organ such as the brain age at different rates.32,33”

What the sources say

• Not checked yetcites [32] Schaum, N. et al. Ageing hallmarks exhibit organ-specific temporal signatures. Nature 583, 596–602 (2020). source
• Not checked yetcites [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). source

In the paper

“With regard to intrinsic changes to cells as a driver of tissue aging, a particular cell type in a tissue could change gradually over time in a process of “analog” aging, analogous to how we characterize organismal aging.”

In the paper

“Indeed, in the scRNA-Seq study mentioned above, parenchymal cells in multiple tissues exhibited progressive changes in gene expression with age.49”

What the sources say

• Not checked yetcites [49] Tabula Muris Consortium. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020). source

In the paper

“Even in the case of senescence where multiple different senescent states have been defined,55 they are still modeled as discrete.”

What the sources say

• Not checked yetcites [55] Hernandez-Segura, A. et al. Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol. 27, 2652–2660 (2017). source

In the paper

“In addition, the atlas, as well as the related tissue RNA bulk study,32 demonstrate a change of composition of the cellular constituents.”

What the sources say

• Not checked yetcites [49] Tabula Muris Consortium. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020). source
• Not checked yetcites [32] Schaum, N. et al. Ageing hallmarks exhibit organ-specific temporal signatures. Nature 583, 596–602 (2020). source

In the paper

“Whereas the progression of tissue aging suggests an analog process with such measures as physiological function, gene expression levels, and protein aggregates changing gradually, we know that there are at least some discrete state transitions of cells in a tissue that can underlie this apparent analog decline.”

In the paper

“For example, for the thymus, heart, and other tissues,52,53 there a progressive decline in cell number with age due to apoptotic cell death.”

What the sources say

• Not checked yetcites [52] Goronzy, J. J. & Weyand, C. M. T cell development and receptor diversity during aging. Curr. Opin. Immunol. 17, 468–475 (2005). source
• Not checked yetcites [53] Tower, J. Programmed cell death in aging. Ageing Res. Rev. 23, 90–100 (2015). source

In the paper

“A recent mouse aging cell atlas (Tabula muris senis) further underlines this finding across 23 tissues and organs.49”

What the sources say

• Not checked yetcites [49] Tabula Muris Consortium. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020). source

In the paper

“As an example, senolytic therapy is clearly aimed to enhance healthspan by cells in a particular state, not all cells in an aged tissue.56”

What the sources say

• Not checked yetcites [56] Robbins P. D. et al. Senolytic drugs: reducing senescent cell viability to extend health span. Annu. Rev. Pharmacol. Toxicol. https://doi.org/10.1146/annurev-pharmtox-050120-105018 (2020). source

In the paper

“Indeed, based on scRNA-Seq data, the proportion of cells expressing the senescence marker p16 more than doubled in a number of tissues of old mice compared to young mice in multiple tissues of mouse.49”

What the sources say

• Not checked yetcites [49] Tabula Muris Consortium. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020). source

In the paper

“Notably, multiple tissues exhibited an increase in the numbers and percentages of pro-inflammatory immune cells as a function of age, a conclusion independently drawn in single cell transcriptomic surveys of 7 tissues in aging rats and 3 tissues in aging mice.50,51”

What the sources say

• 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
• 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

In the paper

“The general concept of this kind of spreading proteinopathy from one cell to another, locally, arise from the biology of prions and prion diseases.60”

What the sources say

• Not checked yetcites [60] Prusiner, S. B. Biology and genetics of prions causing neurodegeneration. Annu. Rev. Genet. 47, 601–623 (2013). source

In the paper

“The notion of cell-to-cell spreading of cellular dysfunction is of course not limited to the biology of senescence. This is becoming an increasingly recognized phenomenon in the pathogenesis of neurodegenerative diseases.59”

What the sources say

• Not checked yetcites [59] Davis, A. A., Leyns, C. E. G. & Holtzman, D. M. Intercellular spread of protein aggregates in neurodegenerative disease. Annu. Rev. Cell Dev. Biol. 34, 545–568 (2018). source

In the paper

“As a disease engulfs a tissue, it is likely to lead to local and systemic changes that, themselves, may promote dysfunction on neighboring and distant cells.”

In the paper

“Furthermore, the ability of interventions not only to slow the rate of aging but actually to rejuvenate cells and tissues seemingly by reversing aging processes expands the spectrum of healthspan-promoting treatments.79,80,81,82,83”

What the sources say

• Not checked yetcites [79] Rando, T. A. & Chang, H. Y. Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell 148, 46–57 (2012). source
• Not checked yetcites [80] Villeda, S. A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat. Med. 20, 659–663 (2014). source
• Not checked yetcites [81] Wyss-Coray, T. Ageing, neurodegeneration and brain rejuvenation. Nature 539, 180–186 (2016). source

In the paper

“Based on early work from our laboratories that ushered in a new era of the use of the technique of parabiosis in aging research, it is clear that systemic factors originating from distant tissues in the body are able to either promote or reverse cell and tissue aging phenotypes.63,64,65”

What the sources say

• Not checked yetcites [63] Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005). source
• Not checked yetcites [64] Brack, A. S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007). source
• Not checked yetcites [65] Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011). source

In the paper

“including the demonstration that plasma infusions alone are sufficient to exert these effects,65,69”

What the sources say

• Not checked yetcites [65] Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011). source
• Not checked yetcites [69] Castellano, J. M. et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 544, 488–492 (2017). source

In the paper

“Without a doubt, the aging process renders cells and tissues more susceptible to the pathophysiological processes that underlie these diseases.”

In the paper

“However, it is likely that, for humans, a considerable degree of personalized approaches will be necessary.”

In the paper

“These could potentially accelerate, delay, or even reverse the rate of aging of other tissues in the body.”

In the paper

“This is not an effect on the aging states of the parenchymal cells but certainly results in age-related changes at the tissue level as a consequence of cell composition.”

In the paper

“In this sense, and related to the notion of the spread of aging described above, aging begets aging.”

In the paper

“While seemingly a cell-intrinsic phenomenon, one of the curious features of the pathology of these diseases is the apparent spread of the cellular abnormalities to anatomically connected brain regions.”

What the sources say

• Not checked yetcites [59] Davis, A. A., Leyns, C. E. G. & Holtzman, D. M. Intercellular spread of protein aggregates in neurodegenerative disease. Annu. Rev. Cell Dev. Biol. 34, 545–568 (2018). source

In the paper

“As with senescence, this phenomenon could represent the conversion of cells from one state (free from aggregates) to another (aggregate-laden) since protein aggregation can be self-propagating.”

In the paper

“but the spread within the central nervous system of an individual suggests cell-to-cell spread.61”

What the sources say

• Not checked yetcites [61] Guo, J. L. & Lee, V. M. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat. Med. 20, 130–138 (2014). source

In the paper

“The secretome of senescent cells has been shown to induce senescence of neighboring cells.58”

What the sources say

• Not checked yetcites [58] Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013). source

In the paper

“Epidemiological data does suggest that individuals with various chronic diseases such as cancer, diabetes, and HIV/AIDS are more likely to develop co-morbidities later in life,72,73,74”

What the sources say

• Not checked yetcites [72] Keating, N. L., Norredam, M., Landrum, M. B., Huskamp, H. A. & Meara, E. Physical and mental health status of older long-term cancer survivors. J. Am. Geriatr. Soc. 53, 2145–2152 (2005). source
• Not checked yetcites [73] Kirkman, M. S. et al. Diabetes in older adults: a consensus report. J. Am. Geriatr. Soc. 60, 2342–2356 (2012). source
• Not checked yetcites [74] High, K. P. et al. HIV and aging: state of knowledge and areas of critical need for research. A report to the NIH Office of AIDS Research by the HIV and Aging Working Group. J. Acquir. Immune Defic. Syndr. 60, S1–S18 (2012). source

In the paper

“In that sense, there can be cellular leaders that accelerate aging of other cells in the tissue.”

In the paper

“Even among highly genetically similar strains of yeast or mice, dietary restriction is equally likely to shorten lifespan as to extend lifespan.76,77,78”

What the sources say

• Not checked yetcites [76] Schleit, J. et al. Molecular mechanisms underlying genotype-dependent responses to dietary restriction. Aging Cell 12, 1050–1061 (2013). source
• Not checked yetcites [77] Rikke, B. A., Liao, C. Y., McQueen, M. B., Nelson, J. F. & Johnson, T. E. Genetic dissection of dietary restriction in mice supports the metabolic efficiency model of life extension. Exp. Gerontol. 45, 691–701 (2010). source
• Not checked yetcites [78] Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V. & Nelson, J. F. Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Aging Cell 9, 92–95 (2010). source

In the paper

“These studies highlight the fact that cellular aging does not occur independently of influences that are both local and systemic.”

In the paper

“consistent with the notion that one disease (or its treatment) may accelerate aging processes more generally, thus rendering individuals more susceptible to other diseases, just as aging itself does.”

In the paper

“distinct patterns of aging among different tissues (as illustrated in Figure 1) cannot be discerned from samples of whole model organisms.”

In the paper

“Likewise, individual patterns of aging cannot be understood from pooled samples.”

In the paper

“Clearly, these temporal patterns cannot be discerned from lifespan studies”