• Open Access

    Roles of poly(ADP-ribose) polymerase 1 and mitophagy in progeroid syndromes as well as physiological ageing

    Naoko Suga
    Yuka Ikeda
    Sayuri Yoshikawa
    Satoru Matsuda *

    Explor Med. 2023;4:822–838 DOI: https://doi.org/10.37349/emed.2023.00180

    Received: May 25, 2023 Accepted: August 10, 2023 Published: October 31, 2023

    Academic Editor: Calogero Caruso, University of Palermo, Italy

    This article belongs to the special issue Determinants of Exceptional Longevity


    Progeroid syndromes are characterized by clinical signs of premature ageing, which may contain several diseases such as Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Hutchinson-Gilford progeria syndrome, and Cockayne syndrome. These disorders may also exhibit some pathological involvements reminiscent of primary mitochondrial diseases. Emerging evidence has linked mitochondria even to physiological ageing. In addition, alterations in the maintenance pathway of mitochondria have been also deliberated as relevant in age-related diseases. In particular, mitophagy and its regulatory pathway might be key process for the homeostasis of mitochondria. Therefore, chronic DNA damage and/or the activation of poly[adenosine diphosphate (ADP)-ribose] polymerase 1 (PARP1) could be a threat to the mitochondrial alterations. The PARP1 is an enzyme responding to the DNA damage, which might be also involved in the mitophagy. Interestingly, the PARP1 has been reported to play an important role in the longevity of lifespan, which has attracted growing attention with the social development. This review may provide a rationalized overview of the involvement of mitochondrial oxidative stresses in genetically defined accelerated ageing, progeroid syndromes, physiological ageing, and/or age-related diseases for the innovative therapeutic approaches.


    Poly(ADP-ribose) polymerase 1 (PARP1), reactive oxygen species, ageing, progeroid syndrome, Werner syndrome, Bloom syndrome, Cockayne syndrome


    The increasing proportion of elderly people in society characterizes an accumulative financial burden because of age-associated diseases and the significant associated cost of health and well-being maintenance [1]. There are broad-ranging suggestions on finding cost-effective interventions for age-associated diseases. Several genetically defined accelerated ageing disorders have been profoundly considered in the comprehension of ageing. Interestingly, all these disorders are associated with some defects in the maintenance of genome. In other words, mutation in DNA repair genes may be involved in the pathogenesis of these genetically ageing disorders [2]. In addition, it is becoming gradually evident that direct or indirect DNA damage by highly reactive oxygen species (ROS) may play central roles in ageing [3]. In fact, the clinical symptoms of progeroid syndromes might be associated with the molecular features of ultraviolet radiation (UVR)-induced oxidative stresses [4]. Moreover, some of these disorders may show neurological involvements reminiscent of which are realized in several mitochondrial illnesses [5]. Mitochondria are the energy factories of the cells. Evolving evidence has connected this organelle to ageing and understanding mitochondrial dysfunction in accelerated ageing diseases [6]. Therefore, an accumulation of damage to mitochondria may trigger the process of accelerated ageing. Furthermore, nuclear DNA damage may lead to enlarged energy consumption, which may also direct to alterations in mitochondrial energy production [7, 8]. Therefore, mitochondrial modifications could secondarily occur in the process of extra DNA repair after the excess DNA damage.

    Mitochondria are an essential part of cells, which may have key roles in a group of metabolic processes including energy production and/or free radical generation. In addition, mitochondria have been considered as significant components in the process of ageing and cell death [9]. Exhausts of cellular energy reserves might lead to mitochondrial dysfunction and/or altered cellular metabolisms [10]. However, mitochondria are flexible organelles capable of varying their function under certain conditions caused by diverse elements of stressors, exercise, and/or diet [11]. In light damage, mitochondria could be repaired by the fusion with intact mitochondria. Otherwise, mitochondria might be segregated and transported to lysosomes for breakdown in the case of severe damage. This mitochondrial recycling is called mitophagy. Mitochondrial dynamics are thought to have important physiological roles in maintaining homeostasis [12]. Therefore, mitophagy has been recognized to be a key process for the homeostasis of mitochondria.

    Several disorders characterized by chronic DNA damage and/or poly[adenosine diphosphate (ADP)-ribose] (PAR) polymerase 1 (PARP1) activation may be at risk for mitochondrial alterations. Consequently, the PARP1 may be involved in the pathogenesis of these disorders with the alteration of mitophagy, which might respond to DNA damage [13]. As the PARP1 is a typical representative of the PARP enzyme family, it would be mentioned hereafter for the explanation of PARP function. The PARP1 could irreversibly cleave nicotinamide adenine dinucleotide (NAD+) generating nicotinamide and monomeric ADP-ribose. The ADP-ribose unit could be poly-elongated in a process of poly(ADP-ribosyl)ation (PARylation), which might be involved in genome repair [14]. Interestingly, increased activation of PARP1 might be involved in the increased adenosine triphosphate (ATP) consumption in the situation of senescence [8]. The PARP1 has been reported to play an important role in longevity [15]. Upon activation of PARP1, some metabolites may inhibit pathways which are usually protective for cells. Then, PARP inhibitors have been suggested for alleviation of inflammation in chronic diseases. Therefore, the inhibition of PARP1 could reverse the phenotypes associated with accelerated ageing [15]. This implies that modulation of the PARP1 pathway might be therapeutic tactics for treating accelerated ageing diseases and/or disorders. In particular, NAD+ levels may have a deep impact on mitochondrial function and/or senescence. It could be speculated that NAD+ levels, PARP1 activation, mitochondrial dysfunction, neurodegenerative diseases, neuron senescence, and/or ageing may propagate a vicious cycle instead of guiding causal and resulting relationship.

    PARP1 is involved in the pathogenesis of progeroid syndromes

    Progeroid syndromes are a cluster of diseases characterized by indications of premature ageing, which may mimic in part physiological ageing [16]. These syndromes comprise several diseases such as Bloom syndrome, Werner syndrome, Hutchinson-Gilford progeria syndrome, Rothmund-Thomson syndrome, and Cockayne syndrome [16], which may exhibit some pathological involvements reminiscent of primary mitochondrial diseases (Figure 1). Mitochondrial illnesses are also a group of genetic diseases categorized by some defects in mitochondrial function [17]. In general, mitochondria are power plants of cells generating cellular energy ATP. Emerging evidence has linked this organelle to physiological ageing and found mitochondrial dysfunction in accelerated ageing disorders. An accumulation of damage to the mitochondria may trigger the process of ageing. Nuclear DNA damage may lead to increased energy consumption, and therefore, the mitochondrial alterations may be secondary to faults in nuclear DNA repair and/or DNA damage [8, 18]. Alterations in mitochondrial ATP production may be caused by the activation of PARP1, an enzyme that responds to DNA damage [19]. Activated PARP1 utilizes key metabolites which may attenuate pathways for the protection of cells. Notably, pharmacological inhibition of PARP1 could reverse the phenotypes related to accelerated ageing [20]. PARP1 may be characterized as a multitasking protein that achieves some signaling functions in the situation of cellular stress response as well as senescence and aging [20]. This suggests that modulation of PARP1 function and/or the related signaling may become a key target of therapeutic tactics for treating accelerated ageing.

    Schematic overview for the pathogenesis of progeroid syndromes such as Rothmund-Thomson syndrome, Werner syndrome, Bloom syndrome, Hutchinson-Gilford progeria syndrome, and Cockayne syndrome. The PARP1, PARPs, and/or NAD+ pools might contribute to the pathogenesis of several progeroid syndromes via the alteration of autophagy and/or mitophagy. Inflammation with several cytokines and/or ROS may be also involved in the modification of autophagy/mitophagy

    Rothmund-Thomson syndrome

    Rothmund-Thomson syndrome is a rare autosomal recessive disorder characterized by premature ageing including skin atrophy, hyperpigmentation, loss of hair, cataracts, and/or skeletal anomalies, which may be associated with increased susceptibility to various cancers. A subset of mutations in the RecQ like helicase 4 gene (RECQL4) has been linked to two types of additional disorders [21]. Gene product of the RECQL4 belongs to a family of DNA helicases that plays an important role in maintaining genomic stability [22]. RECQL4 could interact with PARP1, a nuclear enzyme that also promotes genomic integrity, through its involvement in DNA repair and/or their signaling pathways. The carboxy (C)-terminal region of RECQL4 might be a substrate for PARP1, suggesting an interaction between RECQL4 and PARP1 in response to oxidative stresses [23] (Figures 1 and 2).

    Schematic representation of the modular organization of human PARP1 domains and subdomains. The N-terminal DNA-binding domain contains 3 Zn fingers, which are responsible for DNA binding and some protein-protein interactions. A NLS can be found in this DNA-binding domain. The automodification domain is a central regulating segment with a BRCT, which may serve protein-protein interactions. The C-terminal region accommodates the catalytic centre of PARP1. The WGR domain in the catalytic domain may be important for NAD+ binding. Several key molecules responsible for progeroid syndromes including RECQL4 (Rothmund-Thomson Syndrome), WRN (Werner syndrome), cytidine deaminase (Bloom syndrome), LMNA (Hutchinson-Gilford progeria syndrome), CSB (Cockayne syndrome), might be associated with the PARP1. N: amino; Zn: zinc; NLS: nuclear-localization signal; BRCT: BReast CAncer gene 1 C-terminal; WGR: tryptophan glycine and arginine rich; WRN: Werner syndrome protein; LMNA: lamin A/C; CSB: Cockayne syndrome protein B; CAT: catalase; SIRT1: sirtuin 1; BRCA: BReast CAncer gene; c-Abl: cellular Abelson tyrosine kinase; NF-κB: nuclear factor-kappa B

    Werner syndrome

    Werner syndrome is also a rare autosomal premature ageing disease connected with a predisposition to cancers and/or genomic instability, which might be initiated by some mutations in the gene encoding the WRN, a member of the RecQ family helicases with a potential role in sustaining genomic stability [24]. Loss of the function of a truncated WRN protein in Werner syndrome may result in high levels of early apoptosis exhibited by intensifications of cleaved caspases and/or PARP1. WRN might play an important role in the protection against DNA damage [25]. It has been shown that PARP1 could bind to the N-terminus of WRN and to the C-terminus encompassing the RecQ-conserved domain [26]. In addition, ADP-ribosylation of PARP1 could restore the activity of WRN exonuclease in the presence of NAD+ [26] (Figures 1 and 2).

    Bloom syndrome

    Bloom syndrome is also a rare genetic disease characterized by high levels of chromosomal instability and/or a great increase in cancers risk. Cytidine deaminase expression might be downregulated in cells of Bloom syndrome, possibly leading to decreasing the PARP1 activity [27]. Decrease in the basal activity of PARP1 may contribute to the incomplete sister chromatid disjunction [27, 28]. Therefore, it is possible that PARP1 is involved in sister chromatid disjunction during mitosis [27, 28]. The genetic instability associated with the phenotype of Bloom syndrome may result from a defect of cytidine deaminase [29]. Cytidine deaminase is an enzyme of the pyrimidine salvage pathway, which could decrease the basal activity of PARP1 [30]. The decrease in the PARP1 activity might reduce the efficacy of downstream checkpoints, leading to the increase of unreplicated DNAs during mitosis (Figures 1 and 2).

    Hutchinson-Gilford progeria syndrome

    Hutchinson-Gilford progeria syndrome is a rare autosomal dominant disorder, which is also a fatal developmental disorder characterized by accelerated ageing including bone resorption and/or atherosclerosis [31]. Hutchinson-Gilford progeria syndrome may be caused by sporadic mutations in the LMNA gene, which might produce a mutant LMNA precursor of progerin [32]. Interestingly, the NAD+ salvage pathway has been altered in cells carrying the LMNA mutation, leading to altered PARP1-mediated PARylation [33]. In addition, LMNA could promote the PARP1 mono(ADP-ribosyl)ation in response to DNA damage [34] (Figures 1 and 2).

    Cockayne syndrome

    Cockayne syndrome is a rare autosomal recessive disease described as a segmental premature-aging syndrome. One of the foremost clinical hallmarks of Cockayne syndrome is neurological abnormalities. Mutations in CSB gene are present in the majority of Cockayne syndrome patients. The CSB might be an ATP-dependent chromatin remodeler without helicase activity, which could discharge oxidative stresses by regulating DNA repair pathway. Significantly, the PARP1 could enhance the kinetics of chromatin association with the CSB. In addition, CSB could associate with PARP1 [35]. After the oxidative stresses, CSB and PARP1 could colocalize in the nucleoplasm. poly(ADP)ribosylated (PARylated) PARP1 might be prerequisite for retaining the CSB protein at sites of oxidative DNA damage to facilitate DNA repair [36, 37]. In general, unrepaired oxidative DNA damages have been recognized to increase cancer incidence and premature ageing phenotypes. The regulation of PARP1 by the CSB protein might be a key function in cells with oxidative stresses [38] (Figures 1 and 2).

    Roles of PARP1 in physiological ageing

    As PARP1 utilizes NAD+ as substrate, its extreme activation has an inclusive effect on the NAD+ metabolism in addition to the related intracellular signaling. In general, almost all members (17 members) in the PARPs family could modulate NAD+ metabolism, energy pathways, and/or oxidative metabolism. Reversible PARylation is a pleiotropic controller of several cellular functions [39]. However, uncontrolled PARPs activation may cause cell death. Therefore, noncovalent PARylation could be deliberated as a posttranslational modification of various factors to mitochondrial cell death. Utilizing the oxidized form of NAD+ as a substrate, PARPs could catalyze the covalent binding of ADP-ribose units onto aspartate, glutamate, lysine, serine, and tyrosine residues of various target proteins [40]. ADP-ribosylation might be a well-known posttranslational modification of various proteins with a noticeable regulation of many biological procedures including cellular responses to DNA damage. PARP1 has been defined as one of the fundamental DNA damage-responsive elements required for the preservation of genomic integrity. In response to several DNA damage affected by some genotoxic agents, PARP1 could promote a speedy production of PAR chains required for chromatin relaxation to organize the PAR-binding proteins, DNA repair proteins, and/or several transcription factors [41]. In fact, PARP1 is considerably involved in triggering DNA repair mechanisms [42].

    Mammalian PARP1 consists of three domains such as DNA-binding domain, auto-modification domain, and catalytic domain in the C-terminus [43] (Figure 2). The auto-modification domain in the middle has a BRCA related region, which could promote the recruitment of DNA-repair enzymes. Termed with tryptophan, glycine, and arginine amino acid residues, the WGR domain in the catalytic domain might be important for NAD+ binding [44]. Moreover, c-Abl protein could interact with PARP1, which might be crucial for the expression of inflammatory genes [45]. Furthermore, the PARP1 could influence the expression of inflammatory cytokines including interleukin (IL)-1β and/or tumor necrosis factor (TNF)-α, thus stimulating inflammation [46]. Therefore, for example, excessive activation of PARP1 in microglia may contribute to several neuronal damage, which may be connected to the chronic neuro-inflammation [47]. Besides, acetylation of PARP1 plays an imperative role in several transcriptional regulations [48], which also supports inflammation via the regulation of NF-κB signaling [49]. Together, post-translational modification might be significant in the regulation of PARP1 activity. It has been shown that PARP1 could protect neurons from neuronal cell death under mild oxidative stresses as a result of successful DNA repair [50]. When severe DNA damage occurs, PARP1 may be excessively activated, leading to exhaustion of NAD+ and ATP, and eventually to cell death [51]. SIRT1, which is a NAD+-dependent protein deacetylase, and plays indispensable roles in metabolic control, may be repressed after PARP1 activation. Actually, PARP1 may cooperate with SIRT1 in conditions such as mitochondrial metabolism, DNA damage repair, and/or inflammation [52]. During the course of physiological ageing, SIRT1 activity might be decreased, leading to increased acetylation of PARP1 as well as raised activity of NF-κB [53]. By the same token, it has been demonstrated that PARP1 decreases with cumulative level of progerin in cultured progeria cells [54]. Remarkably, inhibition of PARP1 can improve mitochondrial function through activating the SIRT1 [55]. In addition, PARP1 could contribute to the preservation of blood-brain barrier (BBB) [56] and/or several circadian rhythms in brain [57], which might be linked to the pathogenesis of several neurodegenerative diseases [58]. Accordingly, PARP1 could participate in a diversity of intracellular processes to influence cellular function and/or inflammatory conditions.

    The interaction between PARP1 and adenosine monophosphate-activated protein kinase alpha (AMPKα) has been defined for DNA damage dependent activation of PARP1, while PARP1 might be a target of AMPKα [59]. In addition, an anti-inflammatory crosstalk connecting AMPK to PARP1 activity has been revealed [59]. Consequently, full AMPK activity might be required for PARP1 activation during nutrient deprivation [60]. In PARP1-deficient cells, a decreased production of ROS has been shown even at early time point after starvation [60]. A nuclear quantity of α isoform of AMPK has been defined to be able to interact with PARP1 [15]. Deficiency of effective PARylation might keep the stability of the PARP1/AMPKα complex in PARP1-inactivated cells. Accordingly, the AMPKα could not be transported from the nucleus to the cytosol during the starvation. In consequence, an inefficient activation of the cytosolic AMPKα may incompletely maintain the activity of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) compromising the activation of unc-51 like autophagy activating kinase 1 (ULK1) with the initiation of phagophores [60]. Therefore, the mutual interaction between PARP1 and AMPKα may direct to the optimization of autophagy initiation as a complicated molecular switch via the modification of AMPKα by PARPs [61]. During nutrient deprivation, ROS distributed from mitochondria could induce DNA damage, then PARP1 might make out this DNA damage to encourage DNA repair. In case PARP1 is extremely activated, the cellular condition might consume NAD+ and/or ATP as substrates for synthesizing PAR in cells [62]. As a result, the PARylation of AMPKα by the AMPKα/PARP1 complex might be a key factor in beginning autophagy. Similarly, active AMPKα could activate the autophagy via the inhibition of the mTORC1 complex [63], which might be involved in physiological ageing [36, 37, 55] (Figure 3).

    Several modulator molecules linked to the PI3K/AKT/AMPK/mTOR/mTORC1 signaling pathway for autophagy/mitophagy and/or anti-ageing are demonstrated. Example compounds known to act on the AMPK/mTOR pathway and/or autophagy/mitophagy are also shown on the right side. Arrowhead means stimulation whereas hammerhead represents inhibition. Note that some critical events such as antioxidants feedback pathway have been omitted for clarity. PI3K: phosphoinositide-3 kinase; Gs: G protein stimulatory subunit; AC: adenylate cyclase; PTEN: phosphatase and tensin homologue deleted on chromosome 10; PDK1: phosphoinositide-dependent kinase-1; PKA: protein kinase A; AKT: protein kinase B; MAPK: mitogen-activated protein kinase; mTOR: mammalian/mechanistic target of rapamycin; SCFAs: short chain fatty acids; S6: ribosomal protein S6; S6K: S6 kinase; Nrf2: nuclear factor erythroid 2-related factor 2

    The connection between PARP1 and autophagy/mitophagy

    Mitochondria are like energy plants in a cell. In addition, mitochondria are the main metabolic hubs, which are also involved in signaling pathways for health and/or disease conditions through alterations in these metabolites. Most ROS might be produced in mitochondria, which could work both as signaling and/or detrimental molecules [64]. The resultant oxidative stresses may be also existing in physiological processes for ageing, where they could lead to genomic instability with potential onset of various pathologies. Hence, autophagy/mitophagy might be mandatory in the maintenance of genomic integrity as well as healthy homeostasis [65]. A basal autophagy/mitophagy impairment may lead to inefficient cellular responses to oxidative stresses and increased susceptibility of cells, which could increase cellular vulnerability to external and/or internal stresses [66]. Autophagy/mitophagy might be also mandatory for blocking and/or delaying cell death as well as ageing. As a prosurvival mechanism, autophagy could be encouraged by different types of cellular stresses including DNA damage, ROS, nutrient deprivation, and/or hypoxia, promoting adaptation of cells to the harmful environment [67]. PARP1 might be involved in the regulation of autophagy/mitophagy with PARylation of autophagy/mitophagy-related proteins, where the SIRT1 could be a key regulator of autophagy/mitophagy [68]. Remarkably, several PARPs and PARylation could also modify the function of mitochondria from the nucleus through depletion of NAD+ molecules and/or epigenetic regulation of nuclear genes [69]. Activated PARP1, for example, could regulate some pathological pathways including mitophagy and/or mitochondrial dysfunction [68].

    Mitophagy is an intracellular process through which damaged mitochondria are removed [70]. Mitophagy is a kind of autophagy. Under excess oxidative conditions, massive DNA damage might be recognized by PARP1, triggering the initiation of mitophagy. Again, impaired regulation of autophagy/mitophagy could cause cellular functional decline and/or cell death, bringing about several human diseases [71]. Therefore, autophagy/mitophagy pathways might play crucial roles in keeping the cellular homeostasis [60, 71]. Activated PARP1 may be also accompanied by PARylation-induced depolarization of mitochondrial membrane [72]. In fact, PARP1 could localize to mitochondria, where it poly(ADP)ribosylates (PARylates) electron transport chain proteins [73]. Similar to nuclear PARP1, surplus activation of mitochondrial PARP1 could impede the biogenesis of mitochondria, leading to cell death, which is mitochondria-related apoptosis [74]. DNA damage-dependent mitochondria signaling may be due to the accumulation of PAR [75]. Active PARP1 could synthesize the PAR polymer from NAD+ to mark the site of DNA damage [75]. PARylation is a reversible protein modification carried out by the concerted actions of PARPs and PAR, which could disrupt the mitochondrial energy mechanisms linking the release of mitochondrial proapoptotic factors [76]. It has been shown that PARP1 might play a key role in autophagy/mitophagy by inhibiting SIRT1 [77]. Notably, the SIRT1 might be repressed by the activation of PARP1 [78]. Furthermore, NAD+ precursors could rescue the mitochondrial defects and extend lifespan [78], which may suggest a potential therapeutic strategy for several progeroid disorders [78]. As for a key role in longevity, SIRT1 might be involved in autophagy/mitophagy in physiological and/or pathological ageing. Interestingly, it has been revealed that PARP1-induced defective mitophagy may be also a key mechanism in peripheral neuropathic injuries [79].

    The involvement of impaired mitophagy, NAD+ depletion, and accumulation of damaged mitochondria have been suggested in the metabolic dysfunction of Werner syndrome [80]. Interestingly, renovation of the mitophagy could improve the disease phenotypes of Werner syndrome in both Drosophila melanogaster and Caenorhabditis elegans models as well as in primary cells isolated from patients of Werner syndrome, suggesting that an impairment of the NAD+-mitophagy axis might play a critical role in the development of Werner syndrome [80]. The Bloom syndrome DNA helicase (BLM) is a recombination factor in maintaining genome stability, and BLM-deficient cells may also exhibit increased mitochondrial mass, higher ATP levels, and/or increased respiratory spare capacity [81]. In Cockayne syndrome, cells may exhibit mitochondrial fragmentation and/or excessive fission, which could be rescued by considerably stimulating mitophagy via the overexpression of Parkin [82]. RECQL4 is associated with Rothmund-Thomson syndrome, which could be found in mitochondria [83]. The loss of RECQL4 could also alter the mitochondrial integrity in cells with Rothmund-Thomson syndrome [83]. Remarkably, accumulated evidence indicates that RECQL4 is important not only in cancer development but also in the accelerated ageing process [84]. A basal activation of mitophagy in cells of Hutchinson-Gilford progeria syndrome has been also shown [85]. Interestingly, all of the markers of mitophagy could be reversed in response to the treatment of Hutchinson-Gilford progeria syndrome cells with the specific inhibitor of chromosomal region maintenance 1 (CRM1) [85]. Consistently, the increase of defective mitochondria caused by impaired mitophagy has been also observed in the progeroid syndromes Xeroderma pigmentosum and/or Cockayne [78, 86]. In general, PARP proteins are usually involved in the modification of proteins and/or nucleic acids through mono(ADP-ribosyl)ation or PARylation, which may decrease the activity of AMPK and/or mitochondrial turnover. Lastly in this section, therefore, comprehension of mitochondrial profiles of PARylation, mono(ADP-ribosyl)ation, and the details of AMPK function in the mitochondrial dynamics should be explored in future studies of progeroid disorders.

    Plausible molecular essence of ageing

    Ageing refers to the phenomenon that the physical and psychological adaptability of the body to the environment gradually declines. The increasing proportion of ageing people represents a swelling economic burden, because of age-associated various diseases. Finding potential interventions to age-associated conditions might have widespread implications. A number of genetically defined accelerated ageing diseases have been characterized, which seem to be associated with defects in the maintenance of genomic integrity. As shown here, a key factor that might connect the association between several progeroid disorders and natural ageing may be simultaneously the function of PARPs, oxidative stresses, and/or mitochondrial function. In particular, PARP1 and mitophagy might be important. Emerging evidence has linked mitochondria to physiological ageing and found mitochondrial dysfunction in accelerated ageing disorders [6, 87], which may indicate that an accumulation of damage to the mitochondria could partly underlie the process of ageing. The mitochondrial alterations may be caused by activation of PARP1, which implies that modulation of PARP1 could potentially become a target of therapeutic strategy for treating accelerated ageing disorders and/or age-associated diseases.

    Excessive activation of PARP1 may accelerate ageing in mice model [88]. In line with this finding, PARP1 inhibitor could improve the function of senescent cells by increasing NAD+ levels and/or SIRT1 activity [89]. Actually, NAD+ supplementation in the treatment with nicotinamide riboside or nicotinamide mononucleotide, both of which are NAD+ precursors, has significantly protective effect against the process of ageing [90], as similarly does SIRT1 [91]. Interestingly, it has been shown that both p53 and PARP1 might be responsible for the telomere-shortening [92]. The p53 could control cell cycle, cell apoptosis, and/or senescence instigated by the telomere-shortening [93]. In the telomere-related ageing, PARP1 might be also crucial for the p53 activity [94]. Besides, PARP1 could also prevent for the abnormal telomere shortening as well as the physiological shortening [95]. Therefore, PARP1 inhibition could occasionally induce telomere lengthening [96]. PARP1 may be a pleiotropic molecule in the regulation of ageing. On one hand, PARP1 could protect cells from senescence. On the other hand, PARP1 could also promote cell death in senescent conditions. Increased activity of PARP1 may help to extend lifespan [97]. Importantly, PARP1 has a substantial role in DNA damage-repair, and thereby might contribute to the extension of lifespan in animal models. PARP1 is abundantly expressed in the primary cell cultures derived from long-lived rat species [98]. Consequently, these cells might possess high efficiency in DNA repair ability. Taken together, PARP1 might be a kind of longevity-guarantee factor. It is possible that PARP activity may correlate with maximum lifespan.

    Ageing is a natural process, characterized by progressive loss of biological integrity, impaired function, and increased susceptibility to death. This natural and physiological ageing may be associated with excessive ROS production and/or resulting DNA damage [99]. In this meaning, several antioxidants may have more or less anti-ageing effects. Up to the present, however, studies have focused on the role of mitochondrial dysfunction in ageing and/or ageing-related degenerative diseases, suggesting that restoring mitochondrial biogenesis may exert favourable effects in extending lifespan and/or supporting healthy ageing [100]. Moreover, decreasing levels of autophagy and/or NAD+ have been suggested as further features of ageing or age-related disease [101]. It has been revealed that enhancing autophagy/mitophagy and/or intracellular NAD+ pools could endorse the extension of lifespan [102]. The NAD+ replacement has been shown to alleviate cellular function by enhancing autophagy/mitophagy [103]. Clearance of impaired mitochondria via the mitophagy has been demonstrated to be linked to the longevity [104]. Conversely, impairment of autophagy/mitophagy has been revealed to trigger NAD+ reduction following apoptotic cell death [105]. In other words, both autophagy/mitophagy and NAD+ pools mutually depend on each other for ideal cellular function and/or longevity [106]. Elimination of impaired mitochondria by selective autophagy/mitophagy might be a longevity relevant key process throughout ageing.


    Longevity of lifespan has attracted growing attention as with the social development. In other words, life satisfaction is an imperative provider to the broad construct of subjective well-being both in physical and/or social levels. Public awareness has been elevated about the beneficial potential of specific natural chemical species in the human diet, which should be further focused on the exploration of the precise mechanisms in order to counter the effect of ageing for the longevity. It has been shown that some composition of diet might be one of the major determining factors for longevity of lifespan [107]. In addition, the dietary regulation may contain important, cost-effective, and/or harmless factors to counteract the effect and/or adjust the autophagy/mitophagy. A certain diet could control the autophagy/mitophagy [108], which may also extend the lifespan. For example, it has been reported that downregulation of PARP1 by the puerarin supplementation may be promising for improving the longevity of Drosophila melanogaster by activating autophagy [109]. In mammals, not only has autophagy been associated with the profits of lifespan-extending interventions, but the activation of autophagy may be essentially sufficient to prolong the lifespan in mice [110]. Furthermore, sodium butyrate is known to improve several age-related pathologies and prolongs survival time in mice model [111], which is one of SCFAs detected in several foods. Interestingly, butyrate could promote mitochondrial biogenesis [112]. The anti-senescence activity of genistein is associated with inducing autophagy, in which SIRT1/AMPK pathway might be involved in accelerating autophagy and/or mitigating senescence [113] (Figure 3). Furthermore, an association between longevity and trehalose, a glucose disaccharide, has been recognized [114]. Trehalose could enhance the removal of protein aggregates through the process of autophagy in mammalian cell culture [115]. Disaccharide trehalose might deliver structure-specific effects on cellular energy production with mitochondria [108] (Figure 3). Metformin, a biguanide drug for the treatment of type II diabetes, may have beneficial effects on the lifespan by stimulating autophagy [116] (Figure 3). Additionally, it has been known in a variety of organisms including from yeast to mammals that autophagy might be involved in the regulation of longevity. As a result of the removal of dysfunctional mitochondria, mitophagy could contribute to increased longevity [117]. It seems that prolonged longevity may require autophagy/mitophagy. Consequently, autophagy/mitophagy-stimulating situations provoked by nutritional and/or pharmacologic interventions might contribute to the longevity of lifespan. Remarkably, enhanced autophagy/mitophagy could also counteract ageing of specific organs [118].

    As shown here, quality control of mitochondria has a crucial role in counteracting the process of ageing [119]. Therefore, many cellular components that impact autophagy/mitophagy might be linked to longevity-related molecules such as members of sirtuin family proteins [119]. SIRT1 is the most noticeable member of the sirtuin family, which is a group of class III histone deacetylases implicated in longevity [120]. Some deacetylation genes by SIRT1 in the situation of caloric restriction may impact the longevity of lifespan [121]. For example, nuclear SIRT1 works to deacetylate the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), thereby enabling the expression of genes required in energy-exhausted cells [122]. This modification of histone acetylation might play critical roles in epigenetic gene regulation, which might contribute to the alteration in intracellular metabolism for the longevity of lifespan [122]. Possible causes of ageing might be associated with mitochondria. ROS could lead to damaged DNAs following the accumulation of dysfunctional mitochondria thus increasing autophagy/mitophagy. Therefore, autophagy/mitophagy could be regulated by ROS signaling. As mentioned in the introduction section, NAD+ levels, PARP1 activation, mitochondrial dysfunction, neurodegenerative diseases, neuron senescence, and/or ageing may construct a vicious cycle, whose propagation may drive pathologies. Here, we have highlighted the relationship between PARP1 and autophagy/mitophagy for the deceleration of ageing, which may provide potential therapeutic targets for struggling with age-related diseases and/or promoting longevity.



    adenosine diphosphate


    adenosine monophosphate-activated protein kinase alpha


    adenosine triphosphate




    Cockayne syndrome protein B


    lamin A/C


    mammalian/mechanistic target of rapamycin complex 1




    nicotinamide adenine dinucleotide


    nuclear factor-kappa B


    poly(adenosine diphosphate-ribose)


    poly(adenosine diphosphate-ribose) polymerase 1


    poly(adenosine diphosphate-ribosyl)ation


    RecQ like helicase 4 gene


    reactive oxygen species


    sirtuin 1


    tryptophan glycine and arginine rich


    Werner syndrome protein


    Author contributions

    NS: Conceptualization, Writing—original draft. YI: Conceptualization, Writing—original draft, Visualization. SY: Writing—original draft. SM: Conceptualization, Writing—original draft, Visualization, Supervision. Each author (NS, YI, SY, and SM) has participated sufficiently in this work of drafting the article and/or revising the article for the important rational content. Then, all authors gave final approval of the version to be submitted. Finally, all authors have read and agreed to the published version of the manuscript.

    Conflicts of interest

    The authors declare that they have no conflicts of interest.

    Ethical approval

    Not applicable.

    Consent to participate

    Not applicable.

    Consent to publication

    Not applicable.

    Availability of data and materials

    Not applicable.


    Not applicable.


    © The Author(s) 2023.


    Ye X, Wang M, Xia Y, He P, Zheng X. Direct economic burden attributable to age-related diseases in China: an econometric modelling study. J Glob Health. 2023;13:04042. [DOI] [PubMed] [PMC]
    Yurchenko AA, Rajabi F, Braz-Petta T, Fassihi H, Lehmann A, Nishigori C, et al. Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients. Nat Commun. 2023;14:2561. [DOI] [PubMed] [PMC]
    Wu S, Jiang L, Lei L, Fu C, Huang J, Hu Y, et al. Crosstalk between G-quadruplex and ROS. Cell Death Dis. 2023;14:37. [DOI] [PubMed] [PMC]
    Crochemore C, Fernández-Molina C, Montagne B, Salles A, Ricchetti M. CSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence. Nat Commun. 2019;10:5576. [DOI] [PubMed] [PMC]
    Picca A, Calvani R, Coelho-Junior HJ, Landi F, Bernabei R, Marzetti E. Mitochondrial dysfunction, oxidative stress, and neuroinflammation: intertwined roads to neurodegeneration. Antioxidants (Basel). 2020;9:647. [DOI] [PubMed] [PMC]
    Valencia AP, Whitson JA, Wang S, Nguyen L, den Hartigh LJ, Rabinovitch PS, et al. Aging increases susceptibility to develop cardiac hypertrophy following high sugar consumption. Nutrients. 2022;14:4645. [DOI] [PubMed] [PMC]
    Hershberger KA, Rooney JP, Turner EA, Donoghue LJ, Bodhicharla R, Maurer LL, et al. Early-life mitochondrial DNA damage results in lifelong deficits in energy production mediated by redox signaling in Caenorhabditis elegans. Redox Biol. 2021;43:102000. [DOI] [PubMed] [PMC]
    Scheibye-Knudsen M. Neurodegeneration in accelerated aging. Dan Med J. 2016;63:B5308. [PubMed]
    Yang YD, Li ZX, Hu XM, Wan H, Zhang Q, Xiao R, et al. Insight into crosstalk between mitophagy and apoptosis/necroptosis: mechanisms and clinical applications in ischemic stroke. Curr Med Sci. 2022;42:23748. [DOI] [PubMed]
    Fakouri NB, Hou Y, Demarest TG, Christiansen LS, Okur MN, Mohanty JG, et al. Toward understanding genomic instability, mitochondrial dysfunction and aging. FEBS J. 2019;286:105873. [DOI] [PubMed]
    Verdin E, Hirschey MD, Finley LW, Haigis MC. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci. 2010;35:66975. [DOI] [PubMed] [PMC]
    Marzetti E, Csiszar A, Dutta D, Balagopal G, Calvani R, Leeuwenburgh C. Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics. Am J Physiol Heart Circ Physiol. 2013;305:H45976. [DOI] [PubMed] [PMC]
    Yan Q, Ding J, Khan SJ, Lawton LN, Shipp MA. DTX3L E3 ligase targets p53 for degradation at poly ADP-ribose polymerase-associated DNA damage sites. iScience. 2023;26:106444. [DOI] [PubMed] [PMC]
    Gibson BA, Kraus WL. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol. 2012;13:41124. [DOI] [PubMed]
    Guo S, Zhang S, Zhuang Y, Xie F, Wang R, Kong X, et al. Muscle PARP1 inhibition extends lifespan through AMPKα PARylation and activation in Drosophila. Proc Natl Acad Sci U S A. 2023;120:e2213857120. [DOI] [PubMed] [PMC]
    Oshima J, Kato H, Maezawa Y, Yokote K. RECQ helicase disease and related progeroid syndromes: RECQ2018 meeting. Mech Ageing Dev. 2018;173:803. [DOI] [PubMed] [PMC]
    Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Y, McFarland R, et al. Mitochondrial diseases. Nat Rev Dis Primers. 2016;2:16080. [DOI] [PubMed]
    Feichtinger RG, Sperl W, Bauer JW, Kofler B. Mitochondrial dysfunction: a neglected component of skin diseases. Exp Dermatol. 2014;23:60714. [DOI] [PubMed]
    Kadam A, Jubin T, Roychowdhury R, Garg A, Parmar N, Palit SP, et al. Insights into the functional aspects of poly(ADP-ribose) polymerase-1 (PARP-1) in mitochondrial homeostasis in Dictyostelium discoideum. Biol Cell. 2020;112:22237. [DOI] [PubMed]
    Castedo M, Lafarge A, Kroemer G. Poly(ADP-ribose) polymerase-1 and its ambiguous role in cellular life and death. Cell Stress. 2023;7:16. [DOI] [PubMed] [PMC]
    Lu L, Jin W, Wang LL. RECQ DNA helicases and osteosarcoma. In: Kleinerman E, Gorlick R, editors. Current advances in the science of osteosarcoma. New York (NY): Springer Cham; 2020. pp. 37–54. [DOI] [PubMed]
    Yokoyama H, Moreno-Andres D, Astrinidis SA, Hao Y, Weberruss M, Schellhaus AK, et al. Chromosome alignment maintenance requires the MAP RECQL4, mutated in the Rothmund-Thomson syndrome. Life Sci Alliance. 2019;2:e201800120. [DOI] [PubMed] [PMC]
    Woo LL, Futami K, Shimamoto A, Furuichi Y, Frank KM. The Rothmund-Thomson gene product RECQL4 localizes to the nucleolus in response to oxidative stress. Exp Cell Res. 2006;312:344357. [DOI] [PubMed]
    Oshima J. The Werner syndrome protein: an update. Bioessays. 2000;22:894901. [DOI] [PubMed]
    Ren X, Lim S, Smith MT, Zhang L. Werner syndrome protein, WRN, protects cells from DNA damage induced by the benzene metabolite hydroquinone. Toxicol Sci. 2009;107:36775. [DOI] [PubMed] [PMC]
    von Kobbe C, Harrigan JA, Schreiber V, Stiegler P, Piotrowski J, Dawut L, et al. Poly(ADP-ribose) polymerase 1 regulates both the exonuclease and helicase activities of the Werner syndrome protein. Nucleic Acids Res. 2004;32:400314. [DOI]
    Gemble S, Buhagiar-Labarchède G, Onclercq-Delic R, Jaulin C, Amor-Guéret M. Cytidine deaminase deficiency impairs sister chromatid disjunction by decreasing PARP-1 activity. Cell Cycle. 2017;16:112835. [DOI] [PubMed] [PMC]
    Hoffmann JS, Cordelier P. Proper sister chromatid disjunction requires CDA and PARP-1. Cell Cycle. 2017;16:123940. [DOI] [PubMed] [PMC]
    Chabosseau P, Buhagiar-Labarchède G, Onclercq-Delic R, Lambert S, Debatisse M, Brison O, et al. Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome. Nat Commun. 2011;2:368. [DOI] [PubMed]
    Tallis M, Morra R, Barkauskaite E, Ahel I. Poly(ADP-ribosyl)ation in regulation of chromatin structure and the DNA damage response. Chromosoma. 2014;123:7990. [DOI] [PubMed]
    Pellegrini C, Columbaro M, Capanni C, D’Apice MR, Cavallo C, Murdocca M, et al. All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype. Oncotarget. 2015;6:2991428. [DOI] [PubMed] [PMC]
    Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423:2938. [DOI] [PubMed] [PMC]
    Vignier N, Chatzifrangkeskou M, Morales Rodriguez B, Mericskay M, Mougenot N, Wahbi K, et al. Rescue of biosynthesis of nicotinamide adenine dinucleotide protects the heart in cardiomyopathy caused by lamin A/C gene mutation. Hum Mol Genet. 2018;27:387080. [DOI] [PubMed]
    Ghosh S, Liu B, Wang Y, Hao Q, Zhou Z. Lamin A is an endogenous SIRT6 activator and promotes SIRT6-mediated DNA repair. Cell Rep. 2015;13:1396406. [DOI] [PubMed]
    Thorslund T, von Kobbe C, Harrigan JA, Indig FE, Christiansen M, Stevnsner T, et al. Cooperation of the Cockayne syndrome group B protein and poly(ADP-ribose) polymerase 1 in the response to oxidative stress. Mol Cell Biol. 2005;25:762536. [DOI] [PubMed] [PMC]
    Scheibye-Knudsen M, Mitchell SJ, Fang EF, Iyama T, Ward T, Wang J, et al. A high-fat diet and NAD+ activate Sirt1 to rescue premature aging in Cockayne syndrome. Cell Metab. 2014;20:84055. [DOI] [PubMed] [PMC]
    Guarente L. Linking DNA damage, NAD+/SIRT1, and aging. Cell Metab. 2014;20:7067. [DOI] [PubMed]
    Lake RJ, Bilkis R, Fan HY. Dynamic interplay between Cockayne syndrome protein B and poly(ADP-ribose) polymerase 1 during oxidative DNA damage repair. Biomedicines. 2022;10:361. [DOI] [PubMed] [PMC]
    Eleazer R, Fondufe-Mittendorf YN. The multifaceted role of PARP1 in RNA biogenesis. Wiley Interdiscip Rev RNA. 2021;12:e1617. [DOI] [PubMed] [PMC]
    Vyas S, Matic I, Uchima L, Rood J, Zaja R, Hay RT, et al. Family-wide analysis of poly(ADP-ribose) polymerase activity. Nat Commun. 2014;5:4426. [DOI] [PubMed] [PMC]
    Gupte R, Liu Z, Kraus WL. PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes. Genes Dev. 2017;31:10126. [DOI] [PubMed] [PMC]
    M A, Xavier J, A S F, Bisht P, Murti K, Ravichandiran V, et al. Epigenetic basis for PARP mutagenesis in glioblastoma: a review. Eur J Pharmacol. 2023;938:175424. [DOI] [PubMed]
    Fischbach A, Krüger A, Hampp S, Assmann G, Rank L, Hufnagel M, et al. The C-terminal domain of p53 orchestrates the interplay between non-covalent and covalent poly(ADP-ribosyl)ation of p53 by PARP1. Nucleic Acids Res. 2018;46:80422. [DOI] [PubMed] [PMC]
    Schürch S. Characterization of nucleic acids by tandem mass spectrometry - the second decade (2004–2013): from DNA to RNA and modified sequences. Mass Spectrom Rev. 2016;35:483523. [DOI] [PubMed]
    Bohio AA, Sattout A, Wang R, Wang K, Sah RK, Guo X, et al. c-Abl-mediated tyrosine phosphorylation of PARP1 is crucial for expression of proinflammatory genes. J Immunol. 2019;203:152131. [DOI] [PubMed] [PMC]
    El-Hamoly T, Hegedűs C, Lakatos P, Kovács K, Bai P, El-Ghazaly MA, et al. Activation of poly(ADP-ribose) polymerase-1 delays wound healing by regulating keratinocyte migration and production of inflammatory mediators. Mol Med. 2014;20:36371. [DOI] [PubMed] [PMC]
    Doaee P, Rajaei Z, Roghani M, Alaei H, Kamalinejad M. Effects of Boswellia serrata resin extract on motor dysfunction and brain oxidative stress in an experimental model of Parkinson’s disease. Avicenna J Phytomed. 2019;9:28190. [PubMed] [PMC]
    Hassa PO, Haenni SS, Buerki C, Meier NI, Lane WS, Owen H, et al. Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-κB-dependent transcription. J Biol Chem. 2005;280:4045064. [DOI] [PubMed]
    Faraoni I, Aloisio F, De Gabrieli A, Consalvo MI, Lavorgna S, Voso MT, et al. The poly(ADP-ribose) polymerase inhibitor olaparib induces up-regulation of death receptors in primary acute myeloid leukemia blasts by NF-κB activation. Cancer Lett. 2018;423:12738. [DOI] [PubMed]
    Ke Y, Wang C, Zhang J, Zhong X, Wang R, Zeng X, et al. The role of PARPs in inflammation—and metabolic—related diseases: molecular mechanisms and beyond. Cells. 2019;8:1047. [DOI] [PubMed] [PMC]
    Ponce DP, Salech F, SanMartin CD, Silva M, Xiong C, Roe CM, et al. Increased susceptibility to oxidative death of lymphocytes from Alzheimer patients correlates with dementia severity. Curr Alzheimer Res. 2014;11:8928. [PubMed] [PMC]
    Sebori R, Kuno A, Hosoda R, Hayashi T, Horio Y. Resveratrol decreases oxidative stress by restoring mitophagy and improves the pathophysiology of dystrophin-deficient mdx mice. Oxid Med Cell Longev. 2018;2018:9179270. [DOI] [PubMed] [PMC]
    Ye TJ, Lu YL, Yan XF, Hu XD, Wang XL. High mobility group box-1 release from H2O2-injured hepatocytes due to sirt1 functional inhibition. World J Gastroenterol. 2019;25:543450. [DOI] [PubMed] [PMC]
    Zhang H, Xiong ZM, Cao K. Mechanisms controlling the smooth muscle cell death in progeria via down-regulation of poly(ADP-ribose) polymerase 1. Proc Natl Acad Sci U S A. 2014;111:E226170. [DOI] [PubMed] [PMC]
    Chini CCS, Tarragó MG, Chini EN. NAD and the aging process: role in life, death and everything in between. Mol Cell Endocrinol. 2017;455:6274. [DOI] [PubMed] [PMC]
    Rom S, Zuluaga-Ramirez V, Dykstra H, Reichenbach NL, Ramirez SH, Persidsky Y. Poly(ADP-ribose) polymerase-1 inhibition in brain endothelium protects the blood-brain barrier under physiologic and neuroinflammatory conditions. J Cereb Blood Flow Metab. 2015;35:2836. [DOI] [PubMed] [PMC]
    Sharma A, Lee S, Kim H, Yoon H, Ha S, Kang SU. Molecular crosstalk between circadian rhythmicity and the development of neurodegenerative disorders. Front Neurosci. 2020;14:844. [DOI] [PubMed] [PMC]
    Booth L, Roberts JL, Samuel P, Avogadri-Connors F, Cutler RE, Lalani AS, et al. The irreversible ERBB1/2/4 inhibitor neratinib interacts with the PARP1 inhibitor niraparib to kill ovarian cancer cells. Cancer Biol Ther. 2018;19:52533. [DOI] [PubMed] [PMC]
    Gongol B, Marin T, Peng IC, Woo B, Martin M, King S, et al. AMPKα2 exerts its anti-inflammatory effects through PARP-1 and Bcl-6. Proc Natl Acad Sci U S A. 2013;110:31616. [DOI] [PubMed] [PMC]
    Rodríguez-Vargas JM, Ruiz-Magaña MJ, Ruiz-Ruiz C, Majuelos-Melguizo J, Peralta-Leal A, Rodríguez MI, et al. ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy. Cell Res. 2012;22:118198. [DOI] [PubMed] [PMC]
    Devis-Jauregui L, Eritja N, Davis ML, Matias-Guiu X, Llobet-Navàs D. Autophagy in the physiological endometrium and cancer. Autophagy. 2021;17:107795. [DOI] [PubMed] [PMC]
    Santos SS, Brunialti MKC, Rodrigues LOCP, Liberatore AMA, Koh IHJ, Martins V, et al. Effects of the PARP inhibitor olaparib on the response of human peripheral blood leukocytes to bacterial challenge or oxidative stress. Biomolecules. 2022;12:788. [DOI] [PubMed] [PMC]
    Ara A, Xu A, Ahmed KA, Leary SC, Islam MF, Wu Z, et al. The energy sensor AMPKα1 is critical in rapamycin-inhibition of mTORC1-S6K-induced T-cell memory. Int J Mol Sci. 2022;23:37. [DOI] [PubMed] [PMC]
    Franci L, Tubita A, Bertolino FM, Palma A, Cannino G, Settembre C, et al. MAPK15 protects from oxidative stress-dependent cellular senescence by inducing the mitophagic process. Aging Cell. 2022;21:e13620. [DOI] [PubMed] [PMC]
    Hu C, Zhao L, Shen M, Wu Z, Li L. Autophagy regulation is an effective strategy to improve the prognosis of chemically induced acute liver injury based on experimental studies. J Cell Mol Med. 2020;24:831525. [DOI] [PubMed] [PMC]
    Yakhine-Diop SMS, Morales-García JA, Niso-Santano M, González-Polo RA, Uribe-Carretero E, Martinez-Chacon G, et al. Metabolic alterations in plasma from patients with familial and idiopathic Parkinson’s disease. Aging (Albany NY). 2020;12:16690708. [DOI] [PubMed] [PMC]
    Rodríguez-Vargas JM, Oliver-Pozo FJ, Dantzer F. PARP1 and poly(ADP-ribosyl)ation signaling during autophagy in response to nutrient deprivation. Oxid Med Cell Longev. 2019;2019:2641712. [DOI] [PubMed] [PMC]
    Mao K, Chen J, Yu H, Li H, Ren Y, Wu X, et al. Poly (ADP-ribose) polymerase 1 inhibition prevents neurodegeneration and promotes α-synuclein degradation via transcription factor EB-dependent autophagy in mutant α-synucleinA53T model of Parkinson’s disease. Aging Cell. 2020;19:e13163. [DOI] [PubMed] [PMC]
    Qi H, Price BD, Day TA. Multiple roles for mono- and poly(ADP-ribose) in regulating stress responses. Trends Genet. 2019;35:15972. [DOI] [PubMed] [PMC]
    Tyagi N, Vacek JC, Givvimani S, Sen U, Tyagi SC. Cardiac specific deletion of N-methyl-D-aspartate receptor 1 ameliorates mtMMP-9 mediated autophagy/mitophagy in hyperhomocysteinemia. J Recept Signal Transduct Res. 2010;30:7887. [DOI] [PubMed] [PMC]
    MacVicar TD, Mannack LV, Lees RM, Lane JD. Targeted siRNA screens identify ER-to-mitochondrial calcium exchange in autophagy and mitophagy responses in RPE1 cells. Int J Mol Sci. 2015;16:1335680. [DOI] [PubMed] [PMC]
    Espinoza-Derout J, Shao XM, Bankole E, Hasan KM, Mtume N, Liu Y, et al. Hepatic DNA damage induced by electronic cigarette exposure is associated with the modulation of NAD+/PARP1/SIRT1 axis. Front Endocrinol (Lausanne). 2019;10:320. [DOI] [PubMed] [PMC]
    Brunyanszki A, Szczesny B, Virág L, Szabo C. Mitochondrial poly(ADP-ribose) polymerase: the Wizard of Oz at work. Free Radic Biol Med. 2016;100:25770. [DOI] [PubMed] [PMC]
    Bai P, Cantó C, Oudart H, Brunyánszki A, Cen Y, Thomas C, et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 2011;13:4618. [DOI] [PubMed] [PMC]
    Robinson N, Ganesan R, Hegedűs C, Kovács K, Kufer TA, Virág L. Programmed necrotic cell death of macrophages: focus on pyroptosis, necroptosis, and parthanatos. Redox Biol. 2019;26:101239. [DOI] [PubMed] [PMC]
    Virág L, Robaszkiewicz A, Rodriguez-Vargas JM, Oliver FJ. Poly(ADP-ribose) signaling in cell death. Mol Aspects Med. 2013;34:115367. [DOI] [PubMed]
    Liu T, Yang Q, Zhang X, Qin R, Shan W, Zhang H, et al. Quercetin alleviates kidney fibrosis by reducing renal tubular epithelial cell senescence through the SIRT1/PINK1/mitophagy axis. Life Sci. 2020;257:118116. [DOI] [PubMed]
    Fang EF, Scheibye-Knudsen M, Brace LE, Kassahun H, SenGupta T, Nilsen H, et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+/SIRT1 reduction. Cell. 2014;157:88296. [DOI] [PubMed] [PMC]
    Yuan P, Song F, Zhu P, Fan K, Liao Q, Huang L, et al. Poly (ADP-ribose) polymerase 1-mediated defective mitophagy contributes to painful diabetic neuropathy in the db/db model. J Neurochem. 2022;162:27689. [DOI] [PubMed]
    Gudmundsrud R, Skjånes TH, Gilmour BC, Caponio D, Lautrup S, Fang EF. Crosstalk among DNA damage, mitochondrial dysfunction, impaired mitophagy, stem cell attrition, and senescence in the accelerated ageing disorder Werner syndrome. Cytogenet Genome Res. 2021;161:297304. [DOI] [PubMed] [PMC]
    Subramanian V, Rodemoyer B, Shastri V, Rasmussen LJ, Desler C, Schmidt KH. Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes. Sci Rep. 2021;11:2157. [DOI] [PubMed] [PMC]
    Pascucci B, D’Errico M, Romagnoli A, De Nuccio C, Savino M, Pietraforte D, et al. Overexpression of parkin rescues the defective mitochondrial phenotype and the increased apoptosis of Cockayne Syndrome A cells. Oncotarget. 2017;8:10285267. [DOI] [PubMed] [PMC]
    Croteau DL, Rossi ML, Canugovi C, Tian J, Sykora P, Ramamoorthy M, et al. RECQL4 localizes to mitochondria and preserves mitochondrial DNA integrity. Aging Cell. 2012;11:45666. [DOI] [PubMed] [PMC]
    Lu L, Jin W, Wang LL. Aging in Rothmund-Thomson syndrome and related RECQL4 genetic disorders. Ageing Res Rev. 2017;33:305. [DOI] [PubMed]
    Monterrubio-Ledezma F, Navarro-García F, Massieu L, Mondragón-Flores R, Soto-Ponce LA, Magaña JJ, et al. Rescue of mitochondrial function in Hutchinson-Gilford progeria syndrome by the pharmacological modulation of exportin CRM1. Cells. 2023;12:275. [DOI] [PubMed] [PMC]
    Wang H, Lautrup S, Caponio D, Zhang J, Fang EF. DNA damage-induced neurodegeneration in accelerated ageing and Alzheimer’s disease. Int J Mol Sci. 2021;22:6748. [DOI] [PubMed] [PMC]
    Hobson S, Arefin S, Witasp A, Hernandez L, Kublickiene K, Shiels PG, et al. Accelerated vascular aging in chronic kidney disease: the potential for novel therapies. Circ Res. 2023;132:95069. [DOI] [PubMed]
    Qian M, Liu Z, Peng L, Tang X, Meng F, Ao Y, et al. Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria. Elife. 2018;7:e34836. [DOI] [PubMed] [PMC]
    Zha S, Li Z, Cao Q, Wang F, Liu F. PARP1 inhibitor (PJ34) improves the function of aging-induced endothelial progenitor cells by preserving intracellular NAD+ levels and increasing SIRT1 activity. Stem Cell Res Ther. 2018;9:224. [DOI] [PubMed] [PMC]
    Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9:1286. [DOI] [PubMed] [PMC]
    Meng Q, Guo T, Li G, Sun S, He S, Cheng B, et al. Dietary resveratrol improves antioxidant status of sows and piglets and regulates antioxidant gene expression in placenta by Keap1-Nrf2 pathway and Sirt1. J Anim Sci Biotechnol. 2018;9:34. [DOI] [PubMed] [PMC]
    Beneke S, Cohausz O, Malanga M, Boukamp P, Althaus F, Bürkle A. Rapid regulation of telomere length is mediated by poly(ADP-ribose) polymerase-1. Nucleic Acids Res. 2008;36:630917. [DOI] [PubMed] [PMC]
    Ying Y, Padanilam BJ. Regulation of necrotic cell death: p53, PARP1 and cyclophilin D-overlapping pathways of regulated necrosis? Cell Mol Life Sci. 2016;73:230924. [DOI] [PubMed] [PMC]
    Kanai M, Hanashiro K, Kim SH, Hanai S, Boulares AH, Miwa M, et al. Inhibition of Crm1-p53 interaction and nuclear export of p53 by poly(ADP-ribosyl)ation. Nat Cell Biol. 2007;9:117583. [DOI] [PubMed]
    Rajiah IR, Skepper J. Differential localisation of PARP-1 N-terminal fragment in PARP-1+/+ and PARP-1-/- murine cells. Mol Cells. 2014;37:52631. [DOI] [PubMed] [PMC]
    Harvey A, Mielke N, Grimstead JW, Jones RE, Nguyen T, Mueller M, et al. PARP1 is required for preserving telomeric integrity but is dispensable for A-NHEJ. Oncotarget. 2018;9:3482137. [DOI] [PubMed] [PMC]
    Muiras ML, Müller M, Schächter F, Bürkle A. Increased poly(ADP-ribose) polymerase activity in lymphoblastoid cell lines from centenarians. J Mol Med (Berl). 1998;76:34654. [DOI] [PubMed]
    Evdokimov A, Kutuzov M, Petruseva I, Lukjanchikova N, Kashina E, Kolova E, et al. Naked mole rat cells display more efficient excision repair than mouse cells. Aging (Albany NY). 2018;10:145473. [DOI] [PubMed] [PMC]
    Chen JH, Hales CN, Ozanne SE. DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res. 2007;35:741728. [DOI] [PubMed] [PMC]
    Zhang L, Wu J, Zhu Z, He Y, Fang R. Mitochondrion: a bridge linking aging and degenerative diseases. Life Sci. 2023;322:121666. [DOI] [PubMed]
    Schmauck-Medina T, Molière A, Lautrup S, Zhang J, Chlopicki S, Madsen HB, et al. New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary. Aging (Albany NY). 2022;14:682939. [DOI] [PubMed] [PMC]
    Bjedov I, Cochemé HM, Foley A, Wieser D, Woodling NS, Castillo-Quan JI, et al. Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila. PLoS Genet. 2020;16:e1009083. [DOI] [PubMed] [PMC]
    Camarda G, Jirawatcharadech P, Priestley RS, Saif A, March S, Wong MHL, et al. Antimalarial activity of primaquine operates via a two-step biochemical relay. Nat Commun. 2019;10:3226. [DOI] [PubMed] [PMC]
    Aman Y, Frank J, Lautrup SH, Matysek A, Niu Z, Yang G, et al. The NAD+-mitophagy axis in healthy longevity and in artificial intelligence-based clinical applications. Mech Ageing Dev. 2020;185:111194. [DOI] [PubMed] [PMC]
    Kataura T, Sedlackova L, Otten EG, Kumari R, Shapira D, Scialo F, et al. Autophagy promotes cell survival by maintaining NAD levels. Dev Cell. 2022;57:258498, e1. [DOI] [PubMed]
    Wilson N, Kataura T, Korsgen ME, Sun C, Sarkar S, Korolchuk VI. The autophagy-NAD axis in longevity and disease. Trends Cell Biol. 2023;33:788802. [DOI] [PubMed]
    Shaposhnikov M, Latkin D, Plyusnina E, Shilova L, Danilov A, Popov S, et al. The effects of pectins on life span and stress resistance in Drosophila melanogaster. Biogerontology. 2014;15:11327. [DOI] [PubMed]
    Tsuji A, Yoshikawa S, Ikeda Y, Taniguchi K, Sawamura H, Morikawa S, et al. Tactics with prebiotics for the treatment of metabolic dysfunction-associated fatty liver disease via the improvement of mitophagy. Int J Mol Sci. 2023;24:5465. [DOI] [PubMed] [PMC]
    Kang AW, Sun C, Li HT, Zhong K, Zeng XH, Gu ZF, et al. Puerarin extends the lifespan of Drosophila melanogaster by activating autophagy. Food Funct. 2023;14:214961. [DOI] [PubMed]
    Pyo JO, Yoo SM, Ahn HH, Nah J, Hong SH, Kam TI, et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat Commun. 2013;4:2300. [DOI] [PubMed] [PMC]
    McIntyre RL, Daniels EG, Molenaars M, Houtkooper RH, Janssens GE. From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs. EMBO Mol Med. 2019;11:e9854. [DOI] [PubMed] [PMC]
    Zhang Y, Yu B, Yu J, Zheng P, Huang Z, Luo Y, et al. Butyrate promotes slow-twitch myofiber formation and mitochondrial biogenesis in finishing pigs via inducing specific microRNAs and PGC-1α expression1. J Anim Sci. 2019;97:318092. [DOI] [PubMed] [PMC]
    Zhang H, Yang X, Pang X, Zhao Z, Yu H, Zhou H. Genistein protects against ox-LDL-induced senescence through enhancing SIRT1/LKB1/AMPK-mediated autophagy flux in HUVECs. Mol Cell Biochem. 2019;455:12734. [DOI] [PubMed]
    Seo Y, Kingsley S, Walker G, Mondoux MA, Tissenbaum HA. Metabolic shift from glycogen to trehalose promotes lifespan and healthspan in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2018;115:E2791800. [DOI] [PubMed] [PMC]
    Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and α-synuclein. J Biol Chem. 2007;282:564152. [DOI] [PubMed]
    Xu H, Jia C, Cheng C, Wu H, Cai H, Le W. Activation of autophagy attenuates motor deficits and extends lifespan in a C. elegans model of ALS. Free Radic Biol Med. 2022;181:5261. [DOI] [PubMed] [PMC]
    Eisenberg T, Knauer H, Schauer A, Büttner S, Ruckenstuhl C, Carmona-Gutierrez D, et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009;11:130514. [DOI] [PubMed]
    Madeo F, Zimmermann A, Maiuri MC, Kroemer G. Essential role for autophagy in life span extension. J Clin Invest. 2015;125:8593. [DOI] [PubMed] [PMC]
    Weber TA, Reichert AS. Impaired quality control of mitochondria: aging from a new perspective. Exp Gerontol. 2010;45:50311. [DOI] [PubMed]
    Tang BL. Sirt1 and the mitochondria. Mol Cells. 2016;39:8795. [DOI] [PubMed] [PMC]
    Guarente L. Calorie restriction and sirtuins revisited. Genes Dev. 2013;27:207285. [DOI] [PubMed] [PMC]
    Kaelin WG Jr, McKnight SL. Influence of metabolism on epigenetics and disease. Cell. 2013;153:5669. [DOI] [PubMed] [PMC]