Inflammation, Epigenetics, and Metabolism Converge To Cell Senescence and Ageing - The Regulation and Intervention
Inflammation, Epigenetics, and Metabolism Converge To Cell Senescence and Ageing - The Regulation and Intervention
Inflammation, Epigenetics, and Metabolism Converge To Cell Senescence and Ageing - The Regulation and Intervention
com/sigtrans
Remarkable progress in ageing research has been achieved over the past decades. General perceptions and experimental evidence
pinpoint that the decline of physical function often initiates by cell senescence and organ ageing. Epigenetic dynamics and
immunometabolic reprogramming link to the alterations of cellular response to intrinsic and extrinsic stimuli, representing current
hotspots as they not only (re-)shape the individual cell identity, but also involve in cell fate decision. This review focuses on the
present findings and emerging concepts in epigenetic, inflammatory, and metabolic regulations and the consequences of the
ageing process. Potential therapeutic interventions targeting cell senescence and regulatory mechanisms, using state-of-the-art
techniques are also discussed.
1
Key Laboratory of Ageing and Cancer Biology of Zhejiang Province, Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou, China; 2Key
Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Ageing and Regenerative
Medicine, Jinan University, Guangzhou, China; 3Division of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati,
OH, USA and 4Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA
Correspondence: Hu Wang ([email protected]) or Zhenyu Ju ([email protected])
These authors contributed equally: Xudong Zhu, Zhiyang Chen
These authors jointly supervised this work: Hu Wang, Zhenyu Ju
Fig. 1 Dysregulated inflammation, alteration of epigenetic modifications, and metabolic imbalance converge to cell senescence and ageing.
Cross talks among epigenetic modifiers (writers, readers, and erasers), inflammatory gene expression and immune cell response, and
metabolic alterations contribute to senescent phenotypes and organ degeneration. MiDAS mitochondrial dysfunction-associated senescence,
SASP senescence-associated secretory phenotype, OXPHOS oxidative phosphorylation, ROS reactive oxygen species, TCA tricarboxylic acid
Fig. 3 Inflammatory sources lead to senescence-associated secretory phenotype (SASP). Several pro-inflammatory sources have been
identified to trigger the chronic inflammation during cellular senescence and organismal ageing, featured by the activation of a group of
SASP-related genes, and subsequently the release of SASP components
approaches to attenuate pathophysiological conditions are also aged hematopoietic stem cells (HSCs), further stressing the
discussed, aiming at combating adverse inflammageing. immune system.48 Intriguingly, a study found that the level of
circulating mitochondrial DNA (mtDNA) is significantly increased
Source of chronic inflammation in ageing in elderly individuals and contributes to the increased systemic
High levels of pro-inflammatory cytokines shape the ageing- inflammation, although the exact source for circulating mtDNA
associated pro-inflammatory status, although the source of remains undefined.49
ageing-related chronic low-grade inflammation remains incom-
pletely understood.24,32–34 Nevertheless, a variety of source that Immunosenescence
contributes to the pro-inflammatory microenvironment has been The innate immune system gradually overtakes the adaptive
identified.35 immune system during ageing.50 In general, the function of the
immune system declines with age, collectively termed immuno-
Senescent cells senescence, featured by the reduced output of natural killer cells
Cells are driven into a senescent, nondividing state by many and thymic T cells, decreased phagocytic capacity of macro-
factors, such as telomere shortening, DNA damage, oxidative phages, as well as the impaired activation of neutrophils and
stress, genotoxic stress, and altered chromatin structure.36–39 The maldevelopment of B cells in the aged.50,51 Immunosenescence
immune system efficiently clears away the senescent cells to has been considered a dominating problem in the aged
maintain systemic homeostasis. However, the removal capacity population and is associated with inappropriate immune
declines with age (partially due to the immunosenescence), responses, resulting in the declined removal capability of
resulting in the increased SASP. Therefore, it becomes more senescent cells and DAMPs.52 Reciprocally, inflammageing leads
explicit that SASP builds a relationship connecting cellular to chronic, continuous generation of inflammatory factors that
senescent with various biological processes, where SASP repre- exhausts the adaptive immune responses, culminating with
sents a potential pharmaceutical target to manipulate the immunosenescence.10 Of note, due to the suppression of the
development of ageing and ageing-related diseases (Fig. 3). In adaptive immune response, the innate immune response could be
agreement, mounting evidence suggests that therapeutic removal reinforced as a compensatory means to protect the organism from
of senescent cells could delay or even prevent various age-related infections. Thus, the immunosenescence and inflammageing
diseases, such as atherosclerosis and osteoarthritis.7,20,40,41 could operate in parallel and form a vicious feedback loop.
Cell debris Gut dysbiosis
Cell debris, including damage-associated molecular patterns The gut mucosa barrier plays a vital role in defending against
(DAMPs), damaged organelles, and macromolecules, are recog- bacterial invasion. However, the integrity of the gut is impaired
nized and removed by the immune system. With age, cell debris with age. The permeability of the epithelial cells is damaged,
accumulates due to impaired clearance and overproduction, allowing the bacteria and other toxins to enter the blood, called
inducing augmented inflammation and impairs tissue regenera- “leaky gut”.53–55 The gut microbiota of older people also exhibits a
tion.42,43 The ageing-associated mitochondrial compromise can biased diversity.53–55 For instance, reduced anti-inflammatory
lead to a release of DAMPs, namely the secretory phenotype by bacteria like Bifidobacterium spp., while increased pro-
mitochondrial dysfunction-associated senescence (MiDAS), which inflammatory bacteria like Streptococcus spp. was found in the
causes particular attention in recent years.44–47 Congruently, aged gut.56 These changes lead to an increase in the susceptibility
ageing-associated mitochondrial stress can also lead to aberrant to infections in aged people.57 Another study also shows that gut
activation of inflammasomes and result in a functional decline in microbiota links to longevity, in which healthier seniors showed
Fig. 5 Epigenetic regulators and interventions in ageing. Age-dependent epigenetic remodeling by various (de-)methylases and (de-)
acetylases affects chromatin accessibility, thereby regulating gene transcription and expression. Interventions, such as calorie restriction and
drug treatment, may reverse the age-dependent degeneration in an epigenetic-modifying manner. HDACs histone deacetylases, DNMTs DNA
methyltransferases, TET ten–eleven translocation, HMT histone methyltransferase, TSS transcriptional start site, SAM S-adenosylmethionine, α-
KG alpha-ketoglutarate, NAD nicotinamide adenine dinucleotide
Fig. 6 Intrinsic cues to metabolic reprogramming during ageing. Six aspects, namely protein homeostasis, genetic and epigenetic instability,
organelle dysfunction, redox imbalance, immune response, and altered signaling pathways, lead to the metabolic regulation of ageing
acid chain breakage, increased membrane fluidity, and protein and nonenzyme-based (e.g., vitamins, β-carotene, selenium, GSH/
hydrolysis, inactivation of proteases, etc.). All of the above injuries GSSG, cysteine, etc.) defense systems are required to maintain
can lead to aberrant cellular metabolism and signal transduction, physiological balance. It has been generally accepted that redox
culminating by altering cell fate.357 Consequently, systemic imbalance caused by boosting of ROS and reactive nitrogen
clearance of the excess free radicals through enzyme-based, such species (RNS) production, or “oxidative stress”, and elevated
as SOD2, catalase, glutathione peroxidase, coenzyme Q10, etc.), intracellular NADH:NAD+ ratio, or “reductive stress”, reduced
Fig. 7 Approaches to alter local and systemic metabolism. Six aspects, including environmental stimuli, sleep modulation, exercise, intestinal
microbes, diet, and drug interventions, may reprogram the metabolism thereby benefiting to healthy ageing
Fig. 8 Novel techniques accelerate the discovery of anti-ageing mechanisms and therapies. Illustrations of three advanced approaches, i.e.,
single-cell sequencing, 3D-genome analysis, and genetically encoded fluorescent probes in dissecting genetic, epigenetic, and metabolic
alterations in ageing and anti-ageing research
failure.559 Although heterochronic parabiosis of young and old CR, drug intervention, microbial regulation, and sleep/exercise
mice implies the potential to attenuate the ageing process and represent simple but also noninvasive approaches to extend
improve cell function, how to rejuvenate senescent cells via health span and ameliorate age-related pathologies, at least, via
autologous rather than allogeneic resources remains a central enhancing the tissue function across a broad spectrum of animals
question to avoid issues regarding immunity and ethics. (Fig. 7). The level of CR is indeterminate from individual-by-