Hallmarks of senescence and aging

Dodig, Slavica; Čepelak, Ivana; Pavić, Ivan

doi:10.11613/bm.2019.030501

Cited by 250 publications

(218 citation statements)

References 87 publications

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“…Cellular senescence has been implicated not only in aging itself but also in the onset of age-related disorders, including atherosclerosis, diabetes, and Alzheimer's disease, in cancer, and, more recently, in biological processes such as tissue repair and regeneration and homeostasis of the microenvironment [72,73]. Its role is not restricted to cell growth control but also affects cell-to-cell interactions.…”

Section: Targeting the P53-dependent Senescence In Different Pathophymentioning

confidence: 99%

Role of p53 in the Regulation of Cellular Senescence

et al. 2020

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The p53 transcription factor plays a critical role in cellular responses to stress. Its activation in response to DNA damage leads to cell growth arrest, allowing for DNA repair, or directs cellular senescence or apoptosis, thereby maintaining genome integrity. Senescence is a permanent cell-cycle arrest that has a crucial role in aging, and it also represents a robust physiological antitumor response, which counteracts oncogenic insults. In addition, senescent cells can also negatively impact the surrounding tissue microenvironment and the neighboring cells by secreting pro-inflammatory cytokines, ultimately triggering tissue dysfunction and/or unfavorable outcomes. This review focuses on the characteristics of senescence and on the recent advances in the contribution of p53 to cellular senescence. Moreover, we also discuss the p53-mediated regulation of several pathophysiological microenvironments that could be associated with senescence and its development.Biomolecules 2020, 10, 420 2 of 16 focus on the p53-dependent senescence signaling pathways involved with different stages of senescence and with a consideration for the associated key biomarkers. We also provide an overview on the regulation of p53-mediated cellular senescence in the context of different pathophysiological conditions. Senescence as Cellular Response to StressCellular senescence is defined as a cell state characterized by prolonged and generally irreversible cell-cycle arrest [14] and the acquisition of different phenotypic alterations, including morphological changes, chromatin remodeling, metabolic reprogramming, and secretion of pro-inflammatory factors or SASP (senescence associated secretory phenotypes). These latter count cytokines, growth factors, proteases, and non-soluble extracellular matrix proteins [15]. All these features ultimately limit the replication of both old and damaged cells. Upon physiological conditions, proliferating cells commit to a regular cell cycle [15,16]. On the other hand, both physiological aging, characterized by telomere shortening, and long-term chronic stress, which impairs genomic integrity and stability, could lead to the activation of the senescence pathway [17]. In this sense, the senescence can be viewed as an adaptative response of cells and organisms when exposed to certain unfavorable environmental conditions.Stressors include both intrinsic factors, such as oxidative damage, telomere attrition, hyperproliferation, oncogene activation, and environmental sources, including UV-light, γ-irradiation, and chemotherapeutic drugs [18,19]. Regardless of their origin, the stress factors trigger DNA damage responses (DDR) in the affected cells, which can result in different outcomes, depending on the cell type and the extent of the damage [20]. Mild DNA damage normally induces cell cycle arrest, while severe injury can activate the senescence program or the death programs; the latter includes apoptosis, mitotic catastrophe, autophagy, and necrosis [21].p53 plays a pivotal role in determining the fate of th...

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Section: Targeting the P53-dependent Senescence In Different Pathophymentioning

confidence: 99%

Role of p53 in the Regulation of Cellular Senescence

et al. 2020

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“…It is assumed that administration of mimetics that fulfill all or at least part of these criteria could have a positive impact on healthy life expectancy and longevity. In defining their effects, an important role will be to detect more reliable biomarkers of the aging process itself, since the existing ones still do not meet the criteria of an ideal biomarker 71 . CR mimetics are classified according to mechanisms of action such as AMPK, SIRTs (NAD-boosting compounds included herein), autophagy activators and mTOR inhibitors.…”

Section: Caloric Restriction Mimeticsmentioning

confidence: 99%

Aging, Calorie Restriction and Calorie Restriction Mimetics

Čepelak

Dodig

2019

Rad Hrvatske akademije znanosti i umjetnosti

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In line with the increase in the number of older people in the world, the focus of scientists is directed at examining mechanisms of the aging process as well as establishing strategies/interventions in order to slow down aging and achieve longevity. On preclinical testing models, the most effective strategy for this purpose, as well as for the purpose of delaying age-related diseases, nutritional intervention-restriction of calorie (CR) has been demonstrated, but also some alternative forms of calorie restriction. Possible undesirable effects of restriction are still in the testing phase, and it is known that it is generally difficult to implement in humans. Therefore, the new area of research in gerontology has become the discovery and examination of the effects of compounds that mimic the effects of caloric restriction, so called caloric restriction mimetics (CRM). These compounds include numerous compounds of natural origin but also approved medicaments with certain indications. This overview summarizes the latest data on known mechanisms of caloric restriction and more familiar caloric restriction mimetics. Sažetak:Starenje, kalorijske restrikcije i kalorijsko restrikcijska mimetrika U skladu s povećanjem broja starijih ljudi u svijetu, fokus znanstvenika usmjeren je na ispitivanje mehanizama procesa starenja kao i na uspostavljanje strategija / intervencija kako bi se usporilo starenje i postigla dugovječnost. Na predkliničkim modelima ispitivanja, najučinkovitija strategija za ovu svrhu, kao i za odgađanje bolesti povezanih s dobi, pokazana je prehrambena intervencija -ograničenje kalorija, ali i neki alternativni oblici ograničavanja kalorija. Mogući neželjeni učinci restrikcije još su u fazi ispitivanja, a poznato je da je to općenito teško provesti kod ljudi. Stoga je novo područje istraživanja u gerontologiji postalo otkriće i ispitivanje učinaka spojeva koji oponašaju učinke kalorijske restrikcije, takozvane mimetike kalorijske restrikcije. Ti spojevi uključuju brojne spojeve prirodnog podrijetla, ali i odobrene lijekove s određenim indikacijama. Ovaj pregled sažima najnovije podatke o poznatim mehanizmima kalorijskog ograničenja i poznatijim mimeticima za ograničenje kalorija. ključne

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“…It is now apparent that the principle of SCV, and related machine learning approaches (50), will be essential to understand the role of the client and their associated PN network in managing protein folding in response to aging and to environmental stress related challenges (9). SCV principles will also be critical to understand the functionality of the proteome in the context of genome design and transcriptome responses that generate the protective barriers (3,35) and CARE, as shown herein, that limit or attempt to limit the impact of aging-and pathology-associated stress to achieve a more sustainable level of lung function over a lifespan (13,(89)(90)(91)(92).…”

Section: Discussionmentioning

confidence: 99%

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

Loguercio

Hutt

Campos

et al. 2019

Preprint

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Aging is associated with an increased risk for the development of many diseases. This is exemplified by the increased incidence of lung injury, muscle dysfunction and cognitive impairment in the elderly following influenza infection. Because the infectious cycle of flu is dependent upon the properties of the host, we examined the proteome of alveolar macrophages (AM) and type 2 cells (AT2) obtained from young (3 months) and old (18 months) naïve mice and mice exposed to influenza A. Our proteomics data show that there is a maladaptive collapse of the proteostasis network (PN) and changes in mitochondrial pathways in the aged naïve AM and AT2 proteomes. The mitochondrial imbalance and proteostatic collapse seen in aged cells places an excessive folding burden on these cells, which is further exacerbated following exposure to influenza A. Specifically, we see an imbalance in Hsp70 co-chaperones involved in protein folding and Hsp90 co-chaperones important for stress signaling pathways that are essential for cellular protection during aging. The acute challenge of influenza A infection of young and aged AM and AT2 cells reveals that age-associated changes in the chaperome affect the ability of these cells to properly manage the infection and post-infection biology, contributing to cytotoxicity. We posit that proteomic profiling of individual cell type specific responses provides a high impact approach to pinpoint fundamental molecular relationships that may contribute to the susceptibility to aging and environmental stress, providing a platform to identify new targets for therapeutic intervention to improve resiliency in the elderly.

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Hallmarks of senescence and aging

Cited by 250 publications

References 87 publications

Role of p53 in the Regulation of Cellular Senescence

Role of p53 in the Regulation of Cellular Senescence

Aging, Calorie Restriction and Calorie Restriction Mimetics

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

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