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Cited by 426Cell death mechanisms and regulationGenetics, Aging, and Longevity in Model OrganismsAutophagy in Disease and Therapy

Programmed cell death in aging

Open access
Tower, John·2015·Ageing Research Reviews
DOI 10.1016/j.arr.2015.04.002PMC PMC4480161
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Abstract

Programmed cell death (PCD) pathways, including apoptosis and regulated necrosis, are required for normal cell turnover and tissue homeostasis. Mis-regulation of PCD is increasingly implicated in aging and aging-related disease. During aging the cell turnover rate declines for several highly-mitotic tissues. Aging-associated disruptions in systemic and inter-cell signaling combined with cell-autonomous damage and mitochondrial malfunction result in increased PCD in some cell types, and decreased PCD in other cell types. Increased PCD during aging is implicated in immune system decline, skeletal muscle wasting (sarcopenia), loss of cells in the heart, and neurodegenerative disease. In contrast, cancer cells and senescent cells are resistant to PCD, enabling them to increase in abundance during aging. PCD pathways limit life span in fungi, but whether PCD pathways normally limit adult metazoan life span is not yet clear. PCD is regulated by a balance of negative and positive factors, including the mitochondria, which are particularly subject to aging-associated malfunction.

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Written from the paper’s full text.

TL;DR

Programmed cell death (PCD) is mis-regulated during aging in a cell-type-specific manner, with increased PCD contributing to immune decline, sarcopenia, heart cell loss, and neurodegeneration, while decreased PCD allows cancer and senescent cells to accumulate. Mitochondrial malfunction is proposed as a central underlying factor, and PCD pathways clearly limit life span in fungi but whether they normally limit adult metazoan life span remains unclear.

Key findings

  • Aging is associated with both increased and decreased PCD depending on cell type: increased apoptosis is implicated in thymic involution, T-cell lymphopenia, skeletal muscle wasting, myocyte loss in the heart, and neurodegenerative disease, whereas reduced apoptosis is seen in aging vascular smooth muscle cells, mesenchymal stem cells, and senescent cells.
  • Cancer cells and senescent cells resist PCD; p53 is mutated in the majority of human cancers, and senescent human fibroblasts show failure to reduce Bcl-2, reduced caspase-3, and increased Bcl-xL.
  • Mitochondria are repeatedly implicated in PCD regulation across mammals, Drosophila, C. elegans, and fungi; mitochondrial malfunction, ROS, and decreased mitophagy are proposed to predispose to maladaptive PCD during aging.
  • In fungi, PCD appears to limit life span in both replicative and chronological assays; in C. elegans and Drosophila, canonical caspase-dependent PCD does not appear to limit adult life span, though caspase-independent or necrosis pathways cannot yet be ruled out.

Methods

  • Narrative review synthesizing literature on PCD mechanisms and aging across mammalian systems, Drosophila, C. elegans, Saccharomyces cerevisiae, and Podospora anserina.
  • No primary experimental data are reported; the paper integrates cited studies on apoptosis, regulated necrosis, autophagic cell death, senescence, cancer, neurodegeneration, and life-span regulation.
  • Main analysis is conceptual synthesis, including comparisons of conserved PCD factors and mitochondrial roles across species.

Limitations

  • Stated: whether PCD pathways normally limit adult metazoan life span is not yet clear; possible roles for caspase-independent PCD or necrosis in regulating C. elegans and Drosophila life span cannot yet be ruled out.
  • Stated: precise mechanisms for cell death in aging-associated neurodegenerative diseases are not clear, and the precise mechanisms for sarcopenia are not yet known.
  • Evident: as a narrative review, it does not use a systematic search strategy or quantitative meta-analysis, and many conclusions depend on cited primary studies rather than new data.

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

Integrity signals

Registry

Crossref · 10.1016/j.arr.2015.04.002

Cites

196 of 196 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 147 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Aging is associated with decreased PCD in several cell types.

    “Aging is associated with decreased PCD in several cell types.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Alt et al., 2012 source

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    • cites Wilson et al., 2010 source

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    • cites Suh et al., 2002

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  • Findingcitation

    Some cell types are characterized by increased PCD during aging.

    “Some cell types are characterized by increased PCD during aging.”
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    • cites Sainz et al., 2003 source

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    • cites Gupta, 2005 source

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    • cites Chou and Effros, 2013

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  • Premisenone given

    PCD pathways limit life span in fungi.

    “PCD pathways limit life span in fungi, but whether PCD pathways normally limit adult metazoan life span is not yet clear.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Programmed cell death (PCD) pathways, including apoptosis and regulated necrosis, are required for normal cell turnover and tissue homeostasis.

    “Programmed cell death (PCD) pathways, including apoptosis and regulated necrosis, are required for normal cell turnover and tissue homeostasis.”
    • Also stated in: § 2. PCD in normal tissue development, adult homeostasisand aging · plain
      “In the adult, PCD is required for the normal turnover of cells in numerous tissues that are maintained by cell division, including the intestinal epithelium, the blood, the epidermis, kidney and lungs(Elmore, 2007; Gunther et al., 2013; Kile, 2014).”
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    • cites Gunther et al., 2013 source

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  • Premisecitation

    During aging the cell turnover rate declines for several highly-mitotic tissues.

    “During aging the cell turnover rate declines for several highly-mitotic tissues.”
    • Also stated in: § 2. PCD in normal tissue development, adult homeostasisand aging · plain
      “For example, dramatically decreased cell turnover rate with age is observed for the skin (Rinnerthaler et al., 2014), and reduced cell turnover rates with age are also reported for the heart (Bergmann et al., 2009) breast epithelium (Misell et al., 2005) and pituitary (Nolan et al., 1999; Richardson et al., 2014).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Rinnerthaler et al., 2014

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    • cites Bergmann et al., 2009 source

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  • May combine two claims. 41
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    Findingcitation

    Aging is associated with mis-regulation of PCD, with PCD more active than optimal in some cell types and less active than optimal in others.

    “Aging appears to be associated with mis-regulation of PCD, in that PCD appears to be more active than is optimal in certain cell types, and less active than is optimal in other cell types (Gupta, 2005; Higami and Shimokawa, 2000; Lu et al., 2012; Salminen et al., 2011; Shen and Tower, 2009; Warner, 1997).”
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    • cites Gupta, 2005

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    • cites Lu et al., 2012

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    • Rests on an assumption: There is an optimal level of PCD in young organisms, so deviations during aging constitute mis-regulation.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Cells contain a mix of pro-apoptotic and anti-apoptotic Bcl-2 family proteins and are poised for entry into apoptosis if the balance is sufficiently altered.

    “Cells contain a mix of pro-apoptotic and anti-apoptotic “Bcl-2 family” proteins and are poised for entry into the apoptotic pathway if and when the balance is sufficiently altered.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Increased PCD during aging is implicated in immune system decline, skeletal muscle wasting (sarcopenia), loss of cells in the heart, and neurodegenerative disease.

    “Increased PCD during aging is implicated in immune system decline, skeletal muscle wasting (sarcopenia), loss of cells in the heart, and neurodegenerative disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Aging-associated disruptions in systemic and inter-cell signaling combined with cell-autonomous damage and mitochondrial malfunction result in increased PCD in some cell types, and decreased PCD in other cell types.

    “Aging-associated disruptions in systemic and inter-cell signaling combined with cell-autonomous damage and mitochondrial malfunction result in increased PCD in some cell types, and decreased PCD in other cell types.”
    • Also stated in: § 2. PCD in normal tissue development, adult homeostasisand aging · plain
      “In summary, aging-associated disruptions in systemic and inter-cell signaling combined with cell-autonomous effects result in increased susceptibility to PCD in some cell types, and decreased PCD in other cell types.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Necrotic cell death typically causes a strong immune response, whereas PCD does not.

    “In addition, necrotic cell death typically causes a strong immune response, whereas PCD does not (Proskuryakov and Gabai, 2010; Taylor et al., 2008).”
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    Premisenone given

    PCD is regulated by a balance of negative and positive factors, including the mitochondria, which are particularly subject to aging-associated malfunction.

    “PCD is regulated by a balance of negative and positive factors, including the mitochondria, which are particularly subject to aging-associated malfunction.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Mitochondria play a central role in regulating the apoptotic pathway and caspase activation in mammalian cells.

    “The mitochondria play a central role in regulating the apoptotic pathway and caspase activation in mammalian cells.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    PCD and necrosis mechanisms can sometimes overlap, and necrosis is a more regulated process than was previously assumed.

    “However, more recently it has become clear that the PCD and necrosis mechanisms can sometimes overlap, and that necrosis is a more regulated process than was previously assumed(Galluzzi et al., 2012).”
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    Premisecitation

    In vivo inhibition of caspase activity does not prevent cell death, but shifts the mechanism towards a more necrotic phenotype.

    “Recent studies in mice reveal that in vivo inhibition of caspase activity does not prevent cell death, but rather shifts the mechanism towards a more necrotic phenotype (Galluzzi et al., 2015).”
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    Premisecitation

    PCD is an important anti-cancer mechanism and the p53 pathway is a critical mediator of this response.

    “PCD is an important anti-cancer mechanism and the p53 pathway is a critical mediator of this response (Vazquez et al., 2008).”
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    Premisecitation

    Programmed necrosis is caspase-independent and can be subdivided depending on the involvement of specific factors.

    “Programmed necrosis is caspase-independent and can be further subdivided depending on the involvement of specific factors.”
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    • cites Degterev et al., 2014

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    Premisecitation

    Radiation-induced apoptosis in isolated peripheral blood lymphocytes is significantly reduced in cells isolated from aged mice and from older human patients.

    “Radiation challenge will induce apoptosis in isolated peripheral blood lymphocytes, and this response is significantly reduced in cells isolated from aged mice (Polyak et al., 1997), as well as cells isolated from older human patients (Camplejohn et al., 2003).”
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    Premisecitation

    In humans, aging caused decreased expression of apoptosis genes and increased expression of senescence-related genes in adipose mesenchymal stem cells.

    “For example, in humans, aging caused decreased expression of apoptosis genes and increased expression of senescence-related genes in adipose mesenchymal stem cells (Alt et al., 2012).”
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    Premisecitation

    PCD plays important roles during human development, including the destruction of cells to create the spaces between the digits of the hands and feet, and the structures of the brain.

    “PCD plays important roles during human development, including the destruction of cells to create the spaces between the digits of the hands and feet (Chimal-Monroy et al., 2011; Hernandez-Martinez and Covarrubias, 2011), and the structures of the brain (Burek and Oppenheim, 1996; Oppenheim, 1991).”
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    Premisecitation

    In humans, vascular injury-induced neointima formation is greater in older patients due in part to excessive proliferation and reduced apoptosis of vascular smooth muscle cells, and the same result is observed in aging mice.

    “In humans vascular injury can lead to neointima (scar) formation. This response is greater in older patients due in part to the excessive proliferation and reduced apoptosis of vascular smooth muscle cells (VSMCs), and the same result is observed in aging mice (Vazquez-Padron et al., 2004).”
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    Premisecitation

    Macroautophagy is typically a protective and anti-apoptotic mechanism, and therefore autophagic cell death may involve hyper-activation of a normally beneficial process.

    “Notably, macroautophagy is typically a protective and anti-apoptotic mechanism, and therefore autophagic cell death may involve hyper-activation of a normally beneficial process.”
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    Premisecitation

    During aging there is a significant loss of cells in the thymus (thymus involution) and bone marrow, associated with an age-related increase in the number of apoptotic lymphocytes.

    “During aging there is a significant loss of cells in the thymus (thymus involution) and bone marrow, associated with an age-related increase in the number of apoptotic lymphocytes (Sainz et al., 2003).”
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    Premisecitation

    Resistance to anoikis is a hallmark of metastatic cancers.

    “Anoikis can proceed through either the intrinsic or extrinsic apoptosis pathway depending on the cell type, and importantly, resistance to anoikis is a hallmark of metastatic cancers (Taddei et al., 2012; Zhong and Rescorla, 2012).”
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    Interpretationcitation

    Mis-regulated apoptosis has been implicated in the age-associated increase in fibrotic lung disease in two ways: increased sensitivity to apoptosis in alveolar epithelial cells may lead to greater injury, whereas reduced sensitivity to apoptosis in fibroblasts and myofibroblasts may promote fibrosis.

    “For example, mis-regulated apoptosis has been implicated in the age-associated increase in fibrotic lung disease in two ways: increased sensitivity to apoptosis in alveolar epithelial cells may lead to greater injury, whereas reduced sensitivity to apoptosis in fibroblasts and myofibroblasts may promote fibrosis (Kapetanaki et al., 2013).”
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    Premisecitation

    Aging in the mammalian heart is characterized by a loss of myocytes and hypertrophy of the remaining myocytes.

    “Aging in the mammalian heart is characterized by a loss of myocytes and hypertrophy of the remaining myocytes (Olivetti et al., 1991).”
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    Premisecitation

    Genetic and chemical interventions can preferentially kill senescent cells in vivo in mice, and these interventions had health benefits for mouse models with elevated levels of senescent cells.

    “Recently both genetic and chemical interventions have been described that can preferentially kill senescent cells in vivo in mice, and these interventions had health benefits for mouse models with elevated levels of senescent cells (Zhu et al., 2015).”
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    Premisenone given

    Each of the aging-associated neurodegenerative diseases Alzheimer's disease, Parkinson's disease and Huntington's disease involves the accumulation of abnormal proteins and aggregates.

    “Each of the aging-associated neurodegenerative diseases Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (PD) involves the accumulation of abnormal proteins and aggregates.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    In C. elegans, muscles undergo an aging-related ultrastructural deterioration (sarcopenia), whereas nervous system ultrastructure remains largely intact.

    “In the model organism C. elegans the muscles undergo an aging-related ultrastructural deterioration (also referred to as sarcopenia), whereas nervous system ultrastructure remains largely intact(Herndon et al., 2002).”
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    Interpretationcitation

    Mitochondrial function and oxidative stress are implicated in PCD in the aging heart.

    “In mice, over-expression of the mitochondrial antioxidant enzyme MnSOD reduced PCD in the aging heart, thereby implicating mitochondrial function and oxidative stress (Kwak et al., 2014).”
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    Premisecitation

    Rodent models show decreased levels of Bcl-2 and increases in Bax, cytochrome c and caspase-3 in the aging kidney.

    “For example, the aging kidney has increased sensitivity to stress and PCD, and rodent models show decreased levels of Bcl-2, and increases in Bax, cytochrome c and caspase-3 (Wang et al., 2014).”
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    Premisecitation

    Decreased Bcl-2 and increased ROS are implicated in aging-associated hair greying.

    “Aging-associated hair greying involves loss of melanocyte stem cells by PCD, and decreased Bcl-2 and increased ROS are implicated in this process (Seiberg, 2013).”
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    Premisecitation

    Aging rat gastrocnemius muscle showed increased levels of Bax, decreased Bcl-2, activation of caspase-3 and DNA fragmentation.

    “For example, aging rat gastrocnemius muscle showed increased levels of Bax, decreased Bcl-2, activation of caspase-3 and DNA fragmentation (Song et al., 2006).”
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    Premisecitation

    Olfactory receptor neurons had increased PARP levels and DNA fragmentation, and were sometimes lost through PCD.

    “The olfactory receptor neurons also had increased PARP levels and DNA fragmentation, and were sometimes lost through PCD.”
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    Premisecitation

    The number of neurons does not decrease on a global scale during normal aging in humans or other mammals, indicating a general absence of PCD during normal brain aging.

    “The number of neurons does not decrease on a global scale during normal aging in humans or other mammals, indicating a general absence of PCD during normal brain aging (Andersen et al., 2003; Giannaris and Rosene, 2012; Long et al., 1999; Merrill et al., 2001; Rapp and Gallagher, 1996).”
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    Premisecitation

    Neural tissue is rich in iron, and iron levels increase with age and in neurodegenerative disease.

    “Moreover, neural tissue is rich in iron, and iron levels have been observed to further increase with age and in neurodegenerative disease(Oshiro et al., 2011).”
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    Premisecitation

    The yeast gene Pep4 is related to mammalian cathepsin D, and deletion of Pep4 shortened chronological life span.

    “The yeast gene Pep4 is related to mammalian cathepsin D, and deletion of Pep4 shortened chronological life span.”
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    • cites Carmona-Gutierrez et al., 2011

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    Premisecitation

    Deletion of mitochondrial AIF-like factors PaAIF2 and PaAMID2 caused increased resistance to oxidative stress and increased life span independent of metacaspase activity, indicative of a metacaspase-independent PCD.

    “In addition, deletion of mitochondrial AIF-like factors PaAIF2 and PaAMID2 caused increased resistance to oxidative stress and increased life span independent of metacaspase activity, indicative of a metacaspase-independent PCD (Brust et al., 2010b).”
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    Interpretationreasoning

    Studies with model systems support the conclusion that aging can cause increased susceptibility to apoptosis in some cell types, and decreased apoptosis in other cell types.

    “Taken together the studies with the model systems support the conclusion that aging can cause increased susceptibility to apoptosis in some cell types, and decreased apoptosis in other cell types.”
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    Premisecitation

    Mating type pheromone can induce PCD in S. cerevisiae haploid cells of the corresponding mating type that fail to mate; low levels of hormone promote mating whereas high levels promote PCD.

    “Mating type pheromone can induce PCD in Saccharomyces cerevisiae haploid cells of the corresponding mating type that fail to mate (Severin and Hyman, 2002); low levels of hormone promote mating whereas high levels promote PCD.”
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    Premisecitation

    An IAP-like protein called BIR1 was identified, and over-expression of BIR1 could both reduce PCD and extend chronological life span.

    “An IAP-like protein called BIR1 was identified, and over-expression of BIR1 could both reduce PCD and extend chronological life span (Walter et al., 2006).”
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    Premisecitation

    Deletion of the S. cerevisiae metacaspase YCA1 increased resistance to PCD caused by stressors such as hydrogen peroxide and also increased chronological life span.

    “Deletion of the Saccharomyces cerevisiae metacaspase YCA1 increased resistance to PCD caused by stressors such as hydrogen peroxide and also increased chronological life span (Herker et al., 2004; Madeo et al., 2002).”
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    Premisecitation

    An AIF-like gene called AIF1 was identified and deletion of AIF1 was reported to delay chronological aging.

    “An AIF-like gene called AIF1 was identified and deletion of AIF1 was reported to delay chronological aging (Wissing et al., 2004).”
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    Premisecitation

    Over-expression of YBH3 sensitized cells to PCD caused by hydrogen peroxide, but this death was not dependent upon YCA1, AIF1, NMA111 or NUC1.

    “Over-expression of YBH3 sensitized cells to PCD caused by hydrogen peroxide, however this death was not dependent upon YCA1, AIF1, NMA111 or NUC1.”
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    • cites Buttner et al., 2011

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    Premisecitation

    In mammals, Cyclophilin D interacts with the F1F0-ATP synthase and regulates mitochondrial membrane permeabilization and a programmed-necrosis form of PCD.

    “In mammals, the peptidyl-cis,trans-prolyl-isomerase called Cyclophilin D interacts with the F1F0-ATP synthase and regulates mitochondrial membrane permeabilization and a programmed-necrosis form of PCD (Elrod and Molkentin, 2013; Giorgio et al., 2013).”
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    Premisecitation

    Aged mother cells showed characteristics of PCD including increased markers of ROS, nuclear DNA fragmentation as indicated by TUNEL labeling, and phosphatidylserine externalization as indicated by Annexin V staining.

    “Aged mother cells showed characteristics of PCD including increased markers of ROS, nuclear DNA fragmentation as indicated by TUNEL labeling, and phosphatidylserine externalization as indicated by Annexin V staining (Laun et al., 2001).”
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    Premisecitation

    A yeast homolog of EndoG (NUC1) has opposing roles in cell death in the chronological assay: on glucose media deletion of NUC1 increased cell death, whereas on glycerol media deletion of NUC1 increased life span and increased resistance to hydrogen peroxide induced PCD.

    “A yeast homolog of EndoG was identified (NUC1) that has opposing roles in cell death in the chronological assay: on glucose media deletion of NUC1 increased cell death, whereas on glycerol media deletion of NUC1 increased life span and increased resistance to hydrogen peroxide induced PCD (Buttner et al., 2007).”
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    Premisecitation

    In the replicative aging assay, approaching 25 divisions the mother cell becomes larger, buds less frequently and ultimately dies by lysis.

    “Approaching 25 divisions the mother cell becomes larger, buds less frequently and ultimately dies by lysis(Egilmez and Jazwinski, 1989).”
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    Premisecitation

    The gene DNM1 promoted mitochondrial fission and PCD in response to hydrogen peroxide, whereas the conserved mitochondrial morphology regulator FIS1 inhibited fission and YCA1-dependent cell death.

    “The gene DNM1 promoted mitochondrial fission and PCD in response to hydrogen peroxide, whereas the conserved mitochondrial morphology regulator FIS1 inhibited fission and YCA1-dependent cell death (Fannjiang et al., 2004).”
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  • The paper relies on this without support.

    Changes in PCD markers (such as gene expression, caspase activation, and DNA fragmentation) reflect actual PCD activity and cell loss in aging tissues.

    “The expression of PCD markers correlates with aging and sarcopenia in specific rodent muscle tissues.”

  • The paper relies on this without support.

    Findings from rodent models and cultured cells generalize to human aging.

    “Studies in rodents implicate mitochondrial malfunction and abnormal PCD signaling (Marzetti et al., 2013).”

  • The paper relies on this without support.

    There is an optimal level of PCD in young organisms, so deviations during aging constitute mis-regulation.

    “PCD appears to be more active than is optimal in certain cell types, and less active than is optimal in other cell types”

  • The paper relies on this without support.

    PCD is required for normal tissue homeostasis in the adult.

    “Because PCD is required for normal tissue homeostasis in the adult, it is expected to be important for optimal life span in species such as mammals where multiple tissues are maintained by constant cell turnover.”

  • The paper relies on this without support.

    In mammals, PCD is required for normal development and adult tissue homeostasis.

    “In mammals PCD is required for normal development and adult tissue homeostasis, which complicates investigation of possible roles for PCD in mammalian life span regulation.”

  • The paper relies on this without support.

    The mitochondrial genome has a high mutation rate.

    “The mitochondrial genome has a high mutation rate, and mitochondrial mutations are increasingly implicated in mitochondrial malfunction during aging(Schon et al., 2012; Sevini et al., 2014).”

  • The paper relies on this without support.

    Increasing GDF-11 levels in the aging mouse has a benefit for heart function.

    “Finally, increasing GDF-11 levels in the aging mouse had a benefit for heart function, indicating a role for altered systemic signaling in heart aging.”
7 of 7

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?

  • For the thymus, heart, and other tissues, there is a progressive decline in cell number with age due to apoptotic cell death.

    “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.”

    From Asynchronous, contagious and digital aging (2021) · cites this paper as [53]

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.

  • PD is assigned to two different diseases

    Minor

    The same sentence uses "PD" for both Parkinson's disease and Huntington's disease, making the abbreviation ambiguous.

1 of 1

Cites

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Cited by

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Related

Authors
Tower, J.
Affiliations
University of Southern California (US)
Corresponding author
Tower, John
ORCID
Tower, John
Venue
Ageing Research Reviews
Publisher
Elsevier BV
Published
2015-09
Volume
23
Issue
Pt A
Pages
90-100
ISSN
1568-1637 (ISSN-L)
DOI
10.1016/j.arr.2015.04.002
PMC
PMC4480161
OpenAlex
W2054502486
Semantic Scholar
bb13358b6cc1885d5b506b5f182f4d298bad824e
Cited by
426
References
196
Citations by year
2026: 22 · 2025: 42 · 2024: 79 · 2023: 63 · 2022: 56 · 2021: 43 · 2020: 37 · 2019: 15 · 2018: 21 · 2017: 18 · 2016: 22 · 2015: 8
FWCI
2.23
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Ageing Research Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Department of Health and Human Services (AG011833)
  • Southern California Environmental Health Sciences Center (5P30ES007048)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
programmed cell death, aging, apoptosis, regulated necrosis, cell turnover, tissue homeostasis, mitochondrial dysfunction, immune system decline, sarcopenia, neurodegenerative diseases, cellular senescence, lifespan
MeSH terms
Aging, Animals, Homeostasis, Humans, Cellular Senescence, Cell Death, Apoptosis, Neurodegenerative Diseases

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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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