Basic and translational aging research in China: present and future

The percentage of elderly people in the world is increasing at an unprecedented pace; so it is in China, which has the world's largest population and a high ratio of the seniors (aged 60 and above) to working-age adults. The growing elderly population is presenting a major social challenge. Accordingly, it is not only imperative as a national strategic demand but also promises great scientific values to understand the biological process of aging, explore the mystery of healthy aging, delay the aging process, and treat the age-related diseases. This Perspective summarizes past and present advances of the basic and translational aging research in China and offers perspectives on future endeavors in this area. Based on a national survey conducted by the National Bureau of Statistics, China's elderly population (aged 60 and above) had reached 249 million by the end of 2018, making up about 17.9% of the total population; those aged 65 and above totaled 167 million, accounting for 11.9% of the total population. The 2013 “China Aging Development Report” pointed out that the severity of the aging problems in China was unprecedented. Population aging is accompanied by increased prevalence of various age-related chronic diseases. The cost of healthcare for the elderlies is imposing a heavy financial burden both on the elderlies and their families as well as on society as a whole. It is of great social significance to achieve healthy aging to reduce medical expenses and increase productive engagement of elderly population. The history of aging research in China can be traced back to early 1980s, Chinese scientists began to decode aging. Prof. Tanjun Tong's team discovered the relationship between P16 and telomeres, unraveled the molecular mechanisms by which P16 regulates cellular senescence, and identified genetic indicators and quantitative indices for estimating the “age” of human cells, including telomere length, cell proliferative capacity, senescence-associated β-galactosidase activity, advanced glycation end products, DNA damage repair ability, DNA methylation degree, mitochondrial DNA deletion, and α-2-macroglobulin protein level (Zeng et al., 1999; Duan et al., 2001; Wang et al., 2001; Zhang et al., 2003). In 2005, Liu et al. discovered that a mutation in Lamin A impairs DNA damage repair, thus destabilizing the genome and causing premature cellular aging (Liu et al., 2005). Liu et al. further discovered that Lamin A regulates stem cell self-renewal via the stimulation of the longevity protein SIRT1 (Liu et al., 2012a). Since then, Chinese scientists have been elucidating molecular mechanism, screening drug candidates, and conducting clinical research in the area of aging and degeneration, continuously making progress and filling gaps in the field of aging and degeneration. Over the past ten years, the Chinese government has focused on basic and translational aging research by establishing a number of laboratories, research centers and institutions for aging research and providing significant financial support. The National Natural Science Foundation of China (NSFC) and the Ministry of Science and Technology of China (MOST) supported numerous projects with grants totaling 470.18 million and 917.60 million RMB Yuan from 2007 to 2018, respectively (Fig. 1). Chinese government grant supports to aging research since 2007. (A) NSFC grant supports to aging research. The number of funded projects increased from only a few in 2007 to 156 in 2018; the total amount of grant money increased from several to 90 million RMB Yuan. (B) MOST grant supports to aging research. A total of 37 projects were supported since 2007 with a total grant money of 917.60 million RMB Yuan China has made remarkable progress in aging research that has garnered international recognition over the past decade. In 2016, China launched the Major Program on Organ Aging and Degeneration. Organ aging is accompanied by the progressive decline in organ function. At the cellular level, aging is characterized by the presence of an array of hallmarks, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication (López-Otín et al., 2013). Further progression of organ degeneration leads to the development of age-related diseases. Accordingly, the prognosis and prevention of organ degeneration is critical to the prevention of aging-associated chronic diseases and the primary goal of the Major Program on Organ Aging and Degeneration. The Major Program on Organ Aging and Degeneration aims to answer the following scientific questions: 1) What are the molecular, cellular, and functional changes during aging and progressive degeneration of different organs? 2) How do genetic and environmental factors affect organ aging and degeneration? 3) What are the regulatory mechanisms for organ aging and degeneration during the development of age-related diseases? Towards these questions, the Chinese aging research community have been working collectively with distinct advantages including abundant clinical resources and newly developed technologies. In China, aging biobanks including centenarian collections and brain samples from AD patients have gradually taken shape. Blood samples from 2,178 centenarians and their offsprings have been collected for genetic analysis of a series of age-related diseases, laying the foundations for studying mechanisms and identifying biomarkers for aging and age-related diseases (Zeng et al., 2016). New technologies have also been developed and employed, such as bio-imaging, multi-level “omics” analysis, systems biology modeling and simulation, tissue-specific genetic interventions, stem cell techniques, tissue reconstruction, and premature aging and longevity animal model generation, facilitating the unraveling of molecular mechanisms and therapeutic targets of organ aging and degeneration at the molecular, cellular, tissue, and organism levels. Since its launch in 2016, the Major Program on Organ Aging and Degeneration has greatly promoted the basic and translational aging research in China. The following is a summary of some recent Made-in-China research progress in four aspects. The first is the progress made in genetic and epigenetic regulation of organ aging and degeneration. Aging is a complex biological process. The progression from organ aging to degeneration is collectively influenced by genetic and epigenetic factors. Identification of key tissue-specific aging-related genes, RNAs, proteins, and other biomacromolecules are essential to the mechanistic studies and intervention of human organ aging, as well as to the prognosis and diagnosis of age-related diseases. Limited by insufficient sample size of centenarians, only two genome-wide significant loci, TOMM40/APOE/APOC1 and chromosome 5q33.3, have been found to associate with longevity. Zeng et al. reported a total 11 independent sites associated with longevity in a genome-wide association study (GWAS) on 2,178 Han Chinese centenarians, which is a sample size 1.7 times larger than the previous largest GWAS on centenarians (Sebastiani et al., 2012). Eight independent SNPs and the two aforementioned loci overlapped across the Han Chinese, European, and US populations (Zeng et al., 2016). Approximately 90% of the genome is transcriptionally active, of which only 1.5% encodes proteins. The rest encodes non-protein products such as long-chain non-coding RNAs (lncRNAs) and small ncRNAs including microRNAs (miRNAs), P-element-induced wimpy testis-interacting RNAs (piRNAs), and small interfering RNAs (siRNAs) (Yang et al., 2014; Awan et al., 2017). The majority of lncRNAs are developmental stage-, tissue-, and cell-type-specific. Liu et al. reported 18 lncRNA as well as 14 mRNA modules anatomically diversified by spatial, age, and sex specificities in rhesus macaque brains and characterized the dynamic changes in lncRNA expression during brain development and aging (Liu et al., 2017). Repetitive sequence-enriched genomic regions such as centromeres, telomeres, and most heterochromatin regions are transcriptionally inactive and may even impede replication fork progression, causing replicative stress and disrupting genomic integrity that may lead to aging and tumorigenesis. Mendez-Bermudez et al. reported that telomere-specific protective protein TRF2 stabilizes telomere and peri-centromere regions and is critical to the maintenance of chromosome stability, emphasizing the interconnection between heterochromatin replication and aging (Mendez-Bermudez et al., 2018). Deng et al. revealed that TOE1 interacts with and mediates the 3′ processing of hTR as a 3′-to-5′ exonuclease in conjunction with PARN whereas in TOE1-deficient cells hTR precursors are enriched along with decreased telomerase activity and telomere shortening, elucidating a mechanistic association between TOE1 mutation, abnormal hTR processing, and telomere dysfunction. Interestingly, mutations of PARN and TOE1 have been implicated in human diseases with premature aging phenotypes (Deng et al., 2018). Telomere shortening during cell replication is a major cause of replicative senescence and intensively studied during organ aging and degeneration. Telomeres and telomere-binding proteins form complex secondary nucleoprotein structures that are critical for genome integrity but also present serious challenges during telomere DNA replication. Li et al. reported that the mitotic checkpoint protein BUB3 can bind to telomeres while BUB1 facilitates the recruitment of helicase BLM for telomere DNA replication via the phosphorylation of telomere-binding protein TRF1 (Li et al., 2018). Liu et al. discovered a new telomerase-binding protein ribosomal maturation factor (SBDS) that colocalizes with telomeres and binds to TPP1 as a stabilizer for TPP1-telomerase interaction during DNA replication so as to maintain telomere length, providing a plausible explanation of how SBDS mutations accelerate telomere-length shortening in over 90% of the Shwachman-Diamond Syndrome (SDS) patients (Liu et al., 2018a, b). Tang et al. found that the RNA-binding protein HuR binds to TREC and promotes the methylation (m5C) of TREC at C106, thus enhancing telomerase activity and maintaining the self-renewal ability of murine hematopoietic stem cells. By contrast, in patients with Dyskeratosis congenital (DC) TREC-U100A mutant that interrupts the interaction with HuR impairs telomerase activity and causes shortened telomere, associating HuR with telomerase activity and TERC-linked DC (Tang et al., 2018). Epigenetics of aging provides deep analysis of the epigenetic status of aging, including nucleic acid and histone modifications. In mouse and human brains, Cheng et al. revealed distinct H3K27ac modification patterns in genes differentially regulated with age, and overactivated inflammation-related genes are marked by decreased broad gene-body hyperacetylation (Cheng et al., 2018). Wang et al. reported that hematopoietic stem cells (HSCs) require the histone deacetylase SIRT6 for maintaining homeostasis via the regulation of Wnt signaling (Wang et al., 2016a). Zhang et al. used gene-editing technologies and created genetically engineered SIRT6-deficient monkeys. These monkeys have significantly increased H3K56ac and birth defects as SIRT6 directs neural stem cell differentiation as well as brain development by regulating the expression of imprinting lncRNA H19 (Zhang et al., 2018b). Wang et al. revealed that YTHDF2 facilitates the decay of m6A-modified mRNAs of Wnt target genes in hematopoietic stem cells (HSCs), contributing to the repression of Wnt signaling at steady state. Under hematological stresses, YTHDF2 deficiency blocks the degradation of mRNAs of both Wnt target genes and survival-related genes and increases the number and regenerative capacity of HSCs (Wang et al., 2018a, b). Genetic mutations are associated with the development of accelerated aging and aging-related disorders. Notably, mutations in LMNA and WRN genes lead to aberrant splicing product progerin and protein loss in human premature aging disorders Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS), respectively (Kudlow et al., 2007; Liu et al., 2011a, b; Zhang et al., 2015). Studies on how genetic alteration leads to the cellular and organismal phenotypes of premature aging provide clues to the molecular mechanisms underlying physiological aging and facilitate our understanding of the molecular pathways contributing to healthy aging. Liu's group has generated induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS, Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Fanconi Anemia (FA), and Xeroderma pigmentosum (XP) (Liu et al., 2011a, b, 2012b, 2014a; Fu et al., 2016; Wang et al., 2017). Upon the differentiation of these disease-specific iPSCs to specific somatic cell types, the latter recapitulated aging/disease-associated and tissue-specific phenotypic defects. Furthermore, using targeted gene-editing techniques, they have successfully corrected the mutated LMNA in HGPS-iPSCs, mutated LRRK2 in PD-iPSCs, mutated FANCA in FA-iPSCs, as well as mutated SOD1 and FUS in ALS-iPSCs (Liu et al., 2011b, 2012b, 2014a; Kubben et al., 2016; Wang et al., 2017). These stem cell-based studies provide important platforms for studying aging/disease mechanisms and developing new therapies (Geng et al., 2018; Wu et al., 2018; Zhang et al., 2018a; Ling et al., 2019). The second aspect is how cellular homeostasis deregulated in organ aging and degeneration. Human organ aging and degeneration are accompanied by the changes in the intracellular and extracellular environments, key metabolic signaling pathways, and cellular senescence induced by free radicals, hormones, and proinflammatory cytokines. Bone diseases, such as osteoarthritis, disc herniation, and osteoporosis, are often related to changes in the intracellular homeostasis of aging organs. 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The is to identifying biomarkers for organ aging and degeneration. biomarkers are used in the prognosis and diagnosis of diseases. 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The is to developing new technologies for studying organ aging and degeneration. by the Major Program on Organ Aging and a series of new and technologies have been developed by the scientists in China aging research community to major challenges on organ aging and degeneration. 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The of facilitates the understanding of aging process at the Cheng et al. found that modification distinct regulatory during aging analysis of human and mouse brain epigenetic and expression In H3K27ac are enriched in genes that are with and these are gradually over (Cheng et al., 2018). Liu et al. reported the dynamic changes by and analysis of expression and in developmental and aging macaque brains and found that the expression of lncRNAs are of high and (Liu et al., 2017). Mendez-Bermudez et al. with molecular and and found that the telomere-specific protective protein TRF2 an important in the maintenance of heterochromatin establishing a between telomere and heterochromatin replication (Mendez-Bermudez et al., 2018). The deep of also provides new for aging research. Zhang et al. found that the longevity protein SIRT6 regulates the of stem cell and differentiation as well as the development of et al., 2016; Zhang et al. 2018b). Aging leads to organ degeneration, which may progress age-related diseases. The between organ aging and degeneration provides a critical therapeutic for the prevention and of age-related diseases. the challenges in aging China has launched a broad and research at new factors of organ degeneration, the and progression of age-related diseases, thus healthy aging. the of new such as and protein and aging research be greatly and advanced both in and China. The development of has and analysis at the to the of genome-wide regulatory in cells. was used for the and of stem cells and cell populations obtained from early development et al., Tang et al., as well as for the analysis of and related regulatory during cell and et al., et al., 2016; Han et al., 2018; et al., 2018). 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