Skip to main content

Cell death and senescence

Main text

We are delighted to announce the launch of a new section of the Journal of Translational Medicine on “Cell Death and Senescence”.

Eukaryotic cells exposed to extreme perturbations of homeostasis, which are relatively rare in nature, succumb to the unregulated and virtually immediate physical breakdown of their components, a process that has been dubbed accidental cell death (ACD) [1]. Most often, however, eukaryotic cells are exposed to relatively mild perturbations of their microenvironment, which results in the activation of stress-responsive pathways that are in place to repair macromolecular damage and recover physiological cellular functions [2, 3]. These mechanisms encompass, but are not limited to: the DNA damage response [4], the unfolded protein response [5], and autophagy [6]. When cellular damage can be efficiently repaired and/or microenvironmental perturbations are limited in intensity and duration, cells can recover physiological functions in the context of re-established homeostasis [2, 3]. On the contrary, when damage is beyond repair and/or stressful stimuli are excessively intense or prolonged, the same pathways that initially attempt to restore physiological homeostasis instead engage signaling modules that actively promote cellular demise, a process that has been dubbed regulated cell death (RCD) [1].

As it stands, a number for different RCD modalities has been defined based on key biochemical events [7]. These RCD routines include (but are not limited to): (1) extrinsic and intrinsic apoptosis: two RCD modes involving the activation of proteases of the caspase family that are initiated by perturbation of extracellular and intracellular homeostasis, respectively, with the latter being demarcated by mitochondrial outer membrane permeabilization (MOMP) [8, 9]; (2) mitochondrial permeability transition (MPT)-driven regulated necrosis, a form of RCD initiating with the rapid permeabilization of the inner mitochondrial membrane via a mechanism that involves peptidylprolyl isomerase F (PPIF, best known as CYPD) [10]; (3) necroptosis, a type of regulated necrosis that relies on a signaling core platform involving receptor interacting serine/threonine kinase 3 (RIPK3) and mixed lineage kinase domain like pseudokinase (MLKL) [11]; (4) ferroptosis, an iron-dependent RCD modality that is under tonic inhibition by glutathione peroxidase 4 (GPX4) [12]; and (5) pyroptosis, a variant of necrotic RCD that is demarcated by plasma membrane permeabilization as driven by gasdermin D (GSDMD) or gasdermin E (GSDME) [13, 14].

Importantly, most if not all RCD modalities exhibit a considerable degree of interconnectivity [15], which implies that inhibiting specific components of the system generally delays RCD (and changes its morphological and immunological correlates) but does not prevent it altogether [1]. Moreover, it has now become clear that multiple biochemical mechanisms that were initially considered as the actual drivers of RCD, such as the post-MOMP activation of caspase 3 (CASP3), only control the kinetics of RCD and the interaction of dying cells with the host, but do not determine whether or not RCD will ultimately occur [1, 16]. Intriguingly, such an interaction, which largely (but not exclusively) involves the host immune system, does not emerge only once cells have irremediably committed to death but actually much earlier, during early adaptation to stress (irrespective of whether this will ultimately be successful or not) [17, 18].

Of note, RCD is not the sole mechanism through which multicellular organisms control individual cells that are damaged beyond repair and hence cannot fulfill their functions and perhaps even be dangerous as potentially tumorigenic [3]. Indeed, when eukaryotic cells accumulate somehow intermediate degrees of macromolecular damage, which cannot be efficiently repaired but also do not actively engage RCD, a permanent proliferative arrest associated with a considerable shift in the cellular secretome occurs [19, 20]. This process, which has been dubbed cellular senescence, resembles RCD in that it can also be elicited by perturbations of intracellular or extracellular homeostasis [21]. However, while all senescence inducers cause an irreversible proliferative arrest, the so-called “senescence-associated secretory phenotype” (SASP) exhibits considerable degrees of context dependency [21].

Importantly, dysfunctions in the molecular and cellular mechanisms through which individual eukaryotic cells respond to stress (either successfully or not) and interact with their host in the process, including (but not limited to) the DNA damage response, the unfolded protein response, autophagy, RCD and cellular senescence have been attributed pathological significance in a plethora of human disorders [9, 22]. The new Journal of Translational Medicine section on “Cell Death and Senescence” now opens to consider original contributions, review articles and editorials discussing mechanistic and pathophysiological aspects of all these processes.

The Journal of Translational Medicine is committed to providing authors with rapid editorial decisions, not only as novel incoming contributions are evaluated for suitability, novelty, and scientific value by Section and Associate Editors, but also when expert scientists return their criticism as part of the peer-reviewing process. The new section on “Cell Death and Senescence” will embrace this mission to guarantee high quality and competitive publications, and its Editorial Board is very much looking forward to receiving your contributions.

Data availability

Not applicable.


  1. Galluzzi L, Bravo-San Pedro JM, Vitale I, Aaronson SA, Abrams JM, Adam D, Alnemri ES, Altucci L, Andrews D, Annicchiarico-Petruzzelli M, et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 2015;22:58–73.

    Article  CAS  PubMed  Google Scholar 

  2. Gudipaty SA, Conner CM, Rosenblatt J, Montell DJ. Unconventional ways to live and die: cell death and survival in development, homeostasis, and disease. Annu Rev Cell Dev Biol. 2018;34:311–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Galluzzi L, Yamazaki T, Kroemer G. Linking cellular stress responses to systemic homeostasis. Nat Rev Mol Cell Biol. 2018;19:731–45.

    Article  CAS  PubMed  Google Scholar 

  4. Groelly FJ, Fawkes M, Dagg RA, Blackford AN, Tarsounas M. Targeting DNA damage response pathways in cancer. Nat Rev Cancer. 2023;23:78–94.

    Article  CAS  PubMed  Google Scholar 

  5. Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol. 2020;21:421–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yamamoto H, Zhang S, Mizushima N. Autophagy genes in biology and disease. Nat Rev Genet. 2023;24:382–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486–541.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2020;21:85–100.

    Article  CAS  PubMed  Google Scholar 

  9. Vitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, Agostini M, Agostinis P, Alnemri ES, Altucci L, et al. Apoptotic cell death in disease-current understanding of the NCCD 2023. Cell Death Differ. 2023;30:1097–154.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bonora M, Giorgi C, Pinton P. Molecular mechanisms and consequences of mitochondrial permeability transition. Nat Rev Mol Cell Biol. 2022;23:266–85.

    Article  CAS  PubMed  Google Scholar 

  11. Weinlich R, Oberst A, Beere HM, Green DR. Necroptosis in development, inflammation and disease. Nat Rev Mol Cell Biol. 2017;18:127–36.

    Article  CAS  PubMed  Google Scholar 

  12. Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021;22:266–82.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Liu X, Xia S, Zhang Z, Wu H, Lieberman J. Channelling inflammation: gasdermins in physiology and disease. Nat Rev Drug Discov. 2021;20:384–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vandenabeele P, Bultynck G, Savvides SN. Pore-forming proteins as drivers of membrane permeabilization in cell death pathways. Nat Rev Mol Cell Biol. 2023;24:312–33.

    Article  CAS  PubMed  Google Scholar 

  15. Bedoui S, Herold MJ, Strasser A. Emerging connectivity of programmed cell death pathways and its physiological implications. Nat Rev Mol Cell Biol. 2020;21:678–95.

    Article  CAS  PubMed  Google Scholar 

  16. Rothlin CV, Hille TD, Ghosh S. Determining the effector response to cell death. Nat Rev Immunol. 2021;21:292–304.

    Article  CAS  PubMed  Google Scholar 

  17. Marchi S, Guilbaud E, Tait SWG, Yamazaki T, Galluzzi L. Mitochondrial control of inflammation. Nat Rev Immunol. 2023;23:159–73.

    Article  CAS  PubMed  Google Scholar 

  18. Klapp V, Alvarez-Abril B, Leuzzi G, Kroemer G, Ciccia A, Galluzzi L. The DNA damage response and inflammation in cancer. Cancer Discov 2023:OF1–OF25.

  19. Huang W, Hickson LJ, Eirin A, Kirkland JL, Lerman LO. Cellular senescence: the good, the bad and the unknown. Nat Rev Nephrol. 2022;18:611–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Olan I, Narita M. Senescence: an identity crisis originating from deep within the nucleus. Annu Rev Cell Dev Biol. 2022;38:219–39.

    Article  PubMed  Google Scholar 

  21. Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, Campisi J, Collado M, Evangelou K, Ferbeyre G, et al. Cellular senescence: defining a path forward. Cell. 2019;179:813–27.

    Article  CAS  PubMed  Google Scholar 

  22. Klionsky DJ, Petroni G, Amaravadi RK, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cadwell K, Cecconi F, Choi AMK, et al. Autophagy in major human diseases. EMBO J. 2021;40: e108863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references


LG is/has been supported (as a PI unless otherwise indicated) by two Breakthrough Level 2 Grants from the US DoD BCRP (#BC180476P1; #BC210945), by a Grant from the STARR Cancer Consortium (#I16-0064), by a Transformative Breast Cancer Consortium Grant from the US DoD BCRP (#W81XWH2120034, PI: Formenti), by a U54 Grant from NIH/NCI (#CA274291, PI: Deasy, Formenti, Weichselbaum), by the 2019 Laura Ziskin Prize in Translational Research (#ZP-6177, PI: Formenti) from the Stand Up to Cancer (SU2C), by a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Chen-Kiang) Grant from the Leukemia and Lymphoma Society (LLS), by a Rapid Response Grant from the Functional Genomics Initiative (New York, US), by startup funds from the Dept. of Radiation Oncology at Weill Cornell Medicine (New York, US), by industrial collaborations with Lytix Biopharma (Oslo, Norway), Promontory (New York, US) and Onxeo (Paris, France), as well as by donations from Promontory (New York, US), the Luke Heller TECPR2 Foundation (Boston, US), Sotio a.s. (Prague, Czech Republic), Lytix Biopharma (Oslo, Norway), Onxeo (Paris, France), Ricerchiamo (Brescia, Italy), and Noxopharm (Chatswood, Australia).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Lorenzo Galluzzi.

Ethics declarations

Competing interests

LG is/has been holding research contracts with Lytix Biopharma, Promontory and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, and the Luke Heller TECPR2 Foundation, and holds Promontory stock options. MM is a full-time employee of Sonata.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Galluzzi, L., Myint, M. Cell death and senescence. J Transl Med 21, 425 (2023).

Download citation

  • Published:

  • DOI: