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Review
. 2022 Dec 16;7(1):391.
doi: 10.1038/s41392-022-01251-0.

Aging and aging-related diseases: from molecular mechanisms to interventions and treatments

Jun Guo #  1 , Xiuqing Huang #  1 , Lin Dou #  1 , Mingjing Yan #  1 , Tao Shen  2 , Weiqing Tang  3 , Jian Li  4
Affiliations
Review

Aging and aging-related diseases: from molecular mechanisms to interventions and treatments

Jun Guo et al. Signal Transduct _target Ther. .

Abstract

Aging is a gradual and irreversible pathophysiological process. It presents with declines in tissue and cell functions and significant increases in the risks of various aging-related diseases, including neurodegenerative diseases, cardiovascular diseases, metabolic diseases, musculoskeletal diseases, and immune system diseases. Although the development of modern medicine has promoted human health and greatly extended life expectancy, with the aging of society, a variety of chronic diseases have gradually become the most important causes of disability and death in elderly individuals. Current research on aging focuses on elucidating how various endogenous and exogenous stresses (such as genomic instability, telomere dysfunction, epigenetic alterations, loss of proteostasis, compromise of autophagy, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, deregulated nutrient sensing) participate in the regulation of aging. Furthermore, thorough research on the pathogenesis of aging to identify interventions that promote health and longevity (such as caloric restriction, microbiota transplantation, and nutritional intervention) and clinical treatment methods for aging-related diseases (depletion of senescent cells, stem cell therapy, antioxidative and anti-inflammatory treatments, and hormone replacement therapy) could decrease the incidence and development of aging-related diseases and in turn promote healthy aging and longevity.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Timeline of research on aging and aging-related diseases. RHD rheumatic heart disease, PD Parkinson’s disease, AD Alzheimer’s disease, mtDNA mitochondrial DNA, NAD+ nicotinamide adenine dinucleotide, HP heterochronic parabiosis
Fig. 2
Fig. 2
The ten hallmarks of aging are subdivided into three categories: molecular hallmarks (genomic instability, telomere dysfunction, epigenetic alterations, loss of proteostasis, compromise of autophagy, and mitochondrial dysfunction), cellular hallmarks (cellular senescence, stem cell exhaustion, and altered intercellular communication), and systemic alterations (deregulated nutrient sensing). AMPK protein kinase AMP-activated catalytic subunit alpha 1, ATG5: autophagy-related 5, ATG-7 autophagy-related 7, ATP adenosine triphosphate, BECN1 Beclin 1, ER endoplasmic reticulum stress, EVs extracellular vesicles, GBA gut–brain axis, HSF-1 heat shock factor-1, HSP heat shock protein, IGF insulin-like growth factor-1, mtDNA mitochondrial DNA, mRNA messenger RNA, mTOR mechanistic _target of rapamycin kinase, ncRNA noncoding RNA, OXPHOS oxidative phosphorylation, Rb retinoblastoma, ROS, reactive oxygen species, SASP senescence-associated secretory phenotype
Fig. 3
Fig. 3
Iron and copper accumulate in senescent cells. In senescent cells, iron accumulation is due to defective autophagic degradation of ferritin by lysosomes. In addition, in aging cells, FTMT accumulates on the outer membranes of defective mitochondria and promotes mitophagy by specifically interacting with the autophagic cargo receptor NCOA4 coupled to the LC3-II double-membrane phagophore. Furthermore, in senescent cells, reductions in the levels of Atp7a (a copper exporter) block autophagic–lysosomal degradation of copper. Atp7a copper transporter copper-transporting ATPase 1, Ctr1 copper transporter 1, FTMT mitochondrial ferritin, LC3 I cytosolic form of LC3, LC3-II LC3-phosphatidylethanolamine conjugate, mtROS mitochondrial ROS, MVB multivesicular body, NCOA4 nuclear receptor coactivator 4, TFR transferrin receptor
Fig. 4
Fig. 4
Crosstalk between aging and NAFLD in aging-related metabolic disease. Aging is related to impaired insulin sensitivity. Under insulin-resistant conditions, the amount of NEFAs in the circulation that are derived from white adipose tissue lipolysis increases, resulting in fat overload in the liver. Aging-related impairment of autophagy and mitochondrial dysfunction reduce hepatic lipid droplet breakdown and fatty acid β-oxidation, respectively. Moreover, under conditions of aging-related obesity, hepatic DNL increases due to ChREBP pathway activation. These disorders of lipid metabolism result in the pathogenesis of NAFL. Following hepatic lipid metabolic impairment and lipid accumulation, lipotoxicity and ER stress are induced, and mitochondrial function further worsens, leading to oxidative stress, hepatocyte apoptosis, hepatocyte senescence and inflammation and thus promoting the progression of NASH. Senescent hepatocytes secrete proinflammatory cytokines (IL-6, IL-8, TNF-α, and IL-1β) that stimulate resident KCs in the liver. Activated KCs present M1-like proinflammatory activity and secrete cytokines to induce monocyte infiltration into the liver and differentiation into macrophages. Furthermore, impaired resident KCs can induce monocyte differentiation into monocyte-derived KCs to maintain the KC pool in the liver. Both resident KCs and monocyte-derived KCs interact with HSCs and activate HSCs to produce collagen. In addition, dysbiosis of the gut microbiota impairs intestinal permeability; thus, bacteria-derived molecules enter the liver via the portal vein and in turn influence hepatic metabolism and the progression of NAFLD. However, hepatic metabolic impairment and inflammation further worsen insulin resistance and dysbiosis of the gut microbiota. Moreover, hepatic lipid metabolic disorder results in hypercholesterolemia and hypertriglyceridemia, leading to accelerated progression of atherosclerosis. (Fig. 4 includes modified templates from Servier Medical Art (http://www.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License.)
Fig. 5
Fig. 5
Mitochondrial dysfunction contributes to diverse aging-related diseases. With aging, an increase in ROS production in mitochondria leads to oxidative stress, causing oxidative damage to DNA (especially mtDNA), lipids, and proteins. An increased mtDNA mutation rate causes increased frequencies of errors or mutations in mtDNA-encoded enzyme subunits, resulting in impaired OXPHOS. mtDNA is released into the cytoplasm or outside the cell and participates in SASP secretion by activating cGAS-STING pathways. Decreased mitophagy mediated by the PINK1/parkin ubiquitin pathway results in impaired clearance of damaged mitochondria. Reduced mitochondrial biogenesis mediated by PGC1 and NRF decreases the number of newborn mitochondria. During aging, mitochondria show altered quality control changes, Drp1/FIS1-mediated mitochondrial fission decreases, and MFN/OPA-mediated mitochondrial fusion increases, affecting mitochondrial shape and function. The mitophagy defects and mitochondrial dysfunction trigger Aβ and tau accumulation, leading to synaptic dysfunction and cognitive deficits during AD development. The metabolic transition from OXPHOS to glycolysis leads to altered metabolite generation. Mitochondrial pathway-mediated apoptosis is an important form of cell death. Mitochondrial dysfunction contributes to AD, HF, diabetes, OP, OA, presbycusis, NAFLD, COPD, AMD, and atherosclerosis by inducing oxidative stress, inflammation, apoptosis, and metabolic alterations. (Fig. 5 includes modified templates from Servier Medical Art (http://www.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License.)
Fig. 6
Fig. 6
SASP related to various age-related diseases. Senescent cells that have a proinflammatory SASP can cause substantial pathogenic effects, resulting in various aging-related diseases. In the tissue microenvironment, the SASP involves chemokines, cytokines, proteases, and growth factors, which have a range of negative effects on neighboring cells, the surrounding extracellular matrix and other structural components. Senescent cells exhibit increased expression of chemokines, such as CCL2 and MCP1, which promotes the recruitment of monocytes, macrophages and lymphocytes in the vascular endothelium, islets, liver, synovium, and retinas. The accumulation of proinflammatory factors, such as IL-6, IL-1β, TNF-α, and IL-8, exacerbates the pathogenesis of various age-related diseases. Proteases destroy the external BRB and cartilage by inducing matrix degradation in AMD and OA. Growth factors, such as TGF-β and IGF-1, induce the abnormal proliferation of epithelial and stromal cells involved in EMT in BPH. The multifaceted SASP of senescent cells promotes the progression of various diseases and may be a therapeutic _target. (Fig. 6 includes modified templates from Servier Medical Art (http://www.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License.)
Fig. 7
Fig. 7
Molecular mechanisms for proteostasis in aging-related diseases. Aging, genetic mutations, environmental and lifestyle insults, and various other stresses cause increases in the amounts of unfolded, misfolded, and oxidized proteins, which lead to activation of the protein degradation system of the UPS and lysosomal proteolysis (including nonselective autophagy and selective autophagy, such as mitophagy and reticulophagy). Chaperones help refold unfolded proteins and assist in the formation of autophagosomes and ubiquitin-proteasomes. Balanced proteostasis leads to healthy aging and longevity. Disrupted proteostasis induces protein aggregation, cellular organelle function loss, increased ROS production and chronic inflammation, which lead to the development of many aging-related diseases
Fig. 8
Fig. 8
Possible interventions and treatments against aging-related diseases. Proof-of-principle therapeutic strategies used in cell experiments, animal experiments, and clinical trials are shown together. Daily lifestyle changes, such as exercise, dietary interventions, and weight loss, can inhibit aging and reduce the occurrence and development of aging-related diseases, subsequently promoting healthy aging and longevity. Drug therapy is the main strategy _targeting aging. Antiaging drugs exert their effects by reducing the number of senescent cells, alleviating the SASP, and exerting anti-inflammatory and antioxidant effects while affecting multiple signaling pathways. Altering the metabolism or composition of the gut microbiota with drugs or through microbiota transplantation can also inhibit aging and aging-related diseases. Moreover, cell replacement therapy, cell transplantation, gene therapy and immunotherapy can be used to promote healthy aging and longevity and to treat aging-related diseases. mTOR mammalian _target of rapamycin, NAD+ nicotinamide adenine dinucleotide, SGLT2 sodium-glucose cotransporter 2, ER endoplasmic reticulum, BET bromo- and extraterminal
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