Genetics of Aging Plasticity: History
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Contributor:
Jie Zhang
,
Shixiao Wang
,
Baohua Liu

Biological aging is characterized by irreversible cell cycle blockade, a decreased capacity for tissue regeneration, and an increased risk of age-related diseases and mortality. A variety of genetic and epigenetic factors regulate aging, including the abnormal expression of aging-related genes, increased DNA methylation levels, altered histone modifications, and unbalanced protein translation homeostasis. The epitranscriptome is also closely associated with aging. Aging is regulated by both genetic and epigenetic factors, with significant variability, heterogeneity, and plasticity. Understanding the complex genetic mechanisms of aging will aid the identification of aging-related markers, which may in turn aid the development of effective interventions against this process.

  • Genetics
  • Aging
  • cellular senescence

1. Introduction

Throughout the centuries, there are countless examples of human beings attempting to escape the inevitable: the near-ubiquitous reality of aging and death. While such attempts have been in vain thus far, a number of theories regarding the occurrence of aging have been developed. Some believe that aging is determined primarily by genes [1], while others hypothesize that accumulated cellular damage is the main cause of systemic aging [2]. In fact, aging is a complex process resulting from multiple factors, including genetic and epigenetic molecular markers, such as telomere depletion, genomic instability, and epigenetic alterations [3]. With rapid advances being made in experimental techniques, an increasing body of evidence suggests that these genetic and epigenetic factors are not only individually associated with aging, but that they may work together to drive this process.
Cellular senescence is one of the important factors that trigger aging, and it is also the most widely studied target of aging intervention [4]. Hayflick first proposed the concept of cellular senescence, and he found that mammalian cell cultures divide to a certain stage, then appear senescent or die, which known as the Hayflick limit [5]. Cellular senescence is the process by which cellular functional aging leads to irreversible blockade of the cell cycle, and the two key signaling pathways that control the cell cycle are p53- cyclin-dependent kinase (CDK) inhibitor p21WAF1/CIP1-RB and p16INK4A–RB pathways [6]. Senescent cells are characterized by stagnation of DNA replication, increased expression of senescence-associated secretory phenotype (SASP), metabolic abnormalities of mitochondria, and lysosomes, changes in the nucleus, resistance to apoptosis, accumulation of DNA damage, epigenetic changes, etc [7]. Studies have found that the use of senolytic (“seno” is senescent, “lytic” meaning destroying) therapy to remove senescent cells can effectively improve aging [8].

2. The Genetics of Aging

The lifespans of different biological species lie within a relatively stable range, and there are significant differences between species, which are indicated in the databases (Database of animal ageing and longevity) as summarized in (Table 1). Multiple factors contribute to this difference, including the ratio between body size and heart rate, environmental factors, energy uptake, and genetic factors [9]. In terms of genetic factors, whole genome sequencing has revealed that the mutation rate of non-germline somatic cells between species is an important factor affecting lifespan, with the somatic cell mutation rate having a strong inverse relationship with lifespan and no obvious correlation with body size [10]. Another important genetic factor is the telomere, which is a repeating double-stranded fragment located at the end of chromosomes in eukaryotic cells, where it maintains the integrity of chromosomes and contributes to controls cell division cycles [11]. Although the relationship between telomere length and species lifespan is somewhat controversial, increasing the length of telomeres in mice has been demonstrated to prolong their lifespan, and telomere shortening rate is an important factor affecting the lifespan of species [12]. The genetic basis of longevity is also closely associated with sex, age, and environmental factors, with the influence of genes on lifespan depending on sex, age, and genetic effects varying between males and females [13].
It is particularly noteworthy that sex and aging are closely related. Throughout nature, females generally live longer than males [14]. There are currently two main hypotheses that explain differences in lifespan between sexes: one is sex chromosome differences, and the other is mitochondrial DNA asymmetric inheritance [15]. Sex determination is when male and female sex is determined by different combinations of sex chromosomes [16]. Additionally, many studies have found that sex is profound in terms of longevity. Some aging interventions only work for males and not for females, and vice versa [17]. Between environmental conditions and sex-specific fertility costs and hormones are important causes of gender age differences [14].
Table 1. Aging-related genetics and epigenetics databases, accessed on 20 December 2022.
GenAge The ageing gene database https://genomics.senescence.info/genes/index.html [18]
AnAge Database of animal ageing and longevity https://genomics.senescence.info/species/index.html [18]
CellAge Database of Cell Senescence Genes https://genomics.senescence.info/cells/ [19]
LongevityMap Human longevity genetic variants https://genomics.senescence.info/longevity/ [20]
NIA Interventions Testing Program (ITP) Genetics Conserved longevity gene prioritization https://www.systems-genetics.org/itp-longevity [13]
Aging Atlas Transcriptomics
Epigenomics
Single-cell Transcriptomics
Proteomics
Pharmacogenomics
Metabolomics		 https://ngdc.cncb.ac.cn/aging/index [21]
Endogenous and exogenous DNA damage can hinder cell function, and DNA repair mechanisms and specific gene mutations are key factors affecting cellular aging [22]. Previous studies have found that genetic mechanisms also underly the unusual longevity of certain groups. For example, some rare mutations carried by centenarians activate genes that inhibit cancer cell metastasis and promote DNA double-strand repair (DDR) [23]. Furthermore, a GWAS study found that APOE and G protein coupled receptor 78 (GPR78) variants are closely associated with human life expectancy [24]. Whole-exome sequencing (WES) also revealed that rare, longevity-associated coding variants are mainly concentrated in certain pathways of particular relevance to aging. For example, multiple rare variants in the Wnt pathway have been found to counteract the negative effects of APOE4 expression, improving longevity [25]. Aging-related genes and signaling pathways are the core genetic basis of the regulatory network of aging, and the mining of aging-related genes through bioinformatics and experimental exploration of their internal connections will help us unravel the mystery of aging.

2.1. Aging-Related Genes and Signaling Pathways

Aging is the most important risk factor for a broad array of diseases, including neurodegenerative diseases, cardiovascular disease, metabolic syndrome, chronic inflammation, and cancer. Additionally, genetic mutations that delay aging have been also found to delay the onset of age-related diseases [26][27]. Genes that regulate aging are relatively conserved among species and are enriched in certain signaling pathways [6] (Figure 1). The association between aging and disease makes fighting aging an even more attractive proposition; it is likely to fight the occurrence and progression of other diseases as well. In this section, researchers summarize the most important pathways and genes to the aging process.
Genes 14 00329 g001 550
Figure 1. Genetic and signaling mechanisms underlying aging. Aging involves multiple genetic alterations in a range of pathways, including, but not limited to, nutrient sensing, sirtuins, nuclear skeleton proteins, immunity, inflammation and circadian rhythm. PI3K/AKT, AMPK, and mTORC1 serve as the core members of lipid, glucose, and amino acid sensing. Lamin A/C interacts with SIRT1, 6 and 7 to regulate chromatin and intracellular homeostasis. cGAS-STING responds to internal and external nuclear pressures and regulates senescence-associated secretory phenotype (SASP). The feedback regulation of circadian rhythm-associated genes is also affected by other aging-related genes. p16, cyclin-dependent kinase inhibitor 2A; p21, cyclin-dependent kinase inhibitor 1A; p27, cyclin-dependent kinase inhibitor 1B; Rb, retinoblastoma protein.

2.2. Nutrient Sensing

Cells rely on nutrient sensing for both the detection of stresses and, ultimately, their survival [28]. Nutrient availability and perception are important material basis for maintaining cell growth and normal function, and cellular metabolic homeostasis imbalance and cellular senescence complement each other [29]. For example, in Caenorhabditis elegans (C. elegans), mutations in the highly conserved daf-2 gene, which encodes an insulin-like receptor and regulates the insulin/insulin-like growth factor 1 (IGF-1) pathway, have been found to significantly prolong lifespan [30]. During aging, the mechanistic target of rapamycin (mTOR) signaling pathway is also important for perceiving stress signals and nutrient sensing, and protein translation [31][32]. Genetically inhibiting the insulin/IGF and mTOR pathways has also been demonstrated to extend mouse lifespan [33].
In 1939, researchers discovered that calorie restriction (CR) can ameliorate aging [34]. CR induces various metabolic changes in the body, and crosstalk between CR and proteins related to nutrient sensing-related pathways is an important reason for ameliorate aging [35]. To date, CR has been shown to extend the lifespan of Saccharomyces cerevisiae, C. elegans, normal and progeria mouse models, and non-human primate rhesus monkeys; at present, CR represents the most effective lifespan-extending intervention across species [36][37][38][39][40][41][42]. This is due to the fact that most molecular pathways involved in longevity are associated with increased stress resistance [43]. Compared with ad libitum access to food (AL), every-other-day feeding (EOD) increases the healthy lifespan of mice. Dietary restriction has also been found to limit the growth of various types of tumors [44]. The phosphatidylinositol-3-kinase (PI3K) pathway, which is a key insulin signaling component, is an important regulator of CR [40][45]. In addition, restricting the amount of branched-chain amino acids (BCAAs), such as leucine, in the diet has also been demonstrated to prolong the lifespan of LmnaG609G/G609G and Lmna–/– mice. In terms of physiological aging, a low-BCAA diet reduces weakness, but does not extend lifespan [46]. Thus, achieving CR via the regulation of metabolism and diet represents a promising anti-aging intervention.

2.3. Sirtuins

Sirtuins are another gene family that can extend the lifespan of C. elegans [47]. They are mainly responsible for regulating cell metabolism, genome stability, gene expression, signal transduction, and important for maintaining the health of the body [48]. There are seven sirtuins in mice and humans, and, under CR, SIRT1 expression is upregulated. This prolongs lifespan and is closely associated with the IGF signaling pathway [49]. Meanwhile, SIRT6 regulates the IGF1 levels and, thus, aging, with SIRT6 overexpression extending lifespan in male mice [17]. Recent studies have also confirmed that SIRT1 is a key protein in the regulation of endothelial cell aging; vascular endothelial cells are essential for maintaining the health and growth of blood vessels. Reducing the expression of SIRT1 in endothelial cells accelerates cellular aging and hinders the normal function of blood vessels [50]. Endothelial cell senescence performs a pivotal role in systemic aging, but the effects can be lessened via the overexpression of SIRT7 [51][52]. Furthermore, SIRT6 expression in endothelial cells has been shown to be important for maintaining heart function [53]. Taken together, these findings indicate that aging-related genes show tissue-dependent effects, and targeting specific types of senescent cells may represent an effective way to treat systemic aging.

2.4. Nuclear Skeleton-Associated Proteins

Intranuclear proteins, such as Lamins play an important role in regulating and maintaining the balance of aging and tumors. Mutations in the LMNA gene affect aging through a number of mechanisms. For example, Lamin A/C interacts with SIRT1, 6, and 7 and affects their intracellular activity and stability, thereby regulating aging [52][54][55]. Interactions between Lamin A/C and SIRT7 also inhibit the transcriptional activation of long interspersed elements-1 (LINE-1, L1) [56], which stabilizes heterochromatin structure. This inhibits the development of a SASP, such as a type I interferon response that triggers natural immune pathways, and can therefore delay the aging of human stem cells by reducing inflammation [57]. IGF-1/AKT signaling pathway protects cells from apoptosis [58]. Furthermore, recent studies have found that the abnormally processed progerin, which is classically located within the nucleus, is also localized outside it. Here, it interacts with IGF-1R and downregulates its expression, thereby impairing IGF-1/AKT signaling, inhibits cellular energy metabolism and accelerates cell aging [59]. Inhibiting isoprenylcysteine carboxylmethyltransferase (ICMT)-associated activation of AKT-mTOR signaling has been found to improve progeria symptoms [60]. Notably, an mTOR hypomorphic allele (MtorΔ/+) has also been found to improve aging characteristics and lifespan in LMNAG608G mice [61]. Taken together, these findings indicate that Lamin A and nutrient sensing share an intricate, important connection to the aging process.
Furthermore, another protein from the nuclear matrix, Lamin B1, is also closely related to aging. Cells respond to carcinogenic pressure by degrading Lamin B1 through autophagy, thus accelerating cell senescence [62]. Recent studies have found that intranuclear SIRT1 protein is the second major nuclear substrate for LC3-mediated selective autophagy, thus influencing cellular senescence through this degradation mechanism [63].

2.5. Immunity and Inflammation

Inflammaging is an important component of aging, which is a pathological phenomenon that brings together our knowledge of age-related chronic diseases, functional decline, and weakness [64]. In the process of aging, the innate and acquired immune system is remodeled, and the reliability and efficiency of the immune system decrease with age, which leads to the upregulation of inflammatory response and the occurrence of related degenerative diseases [65]. The drivers of the inflammatory response mainly include two parts: the degradation of immune receptors/immune sensors and the increase in stimuli that trigger inflammation [26][66]. Inflammation is also the result of lifelong exposure of the immune system to antigenic stimuli and complex genetic, environmental, and age-related mechanisms. Inflammation underlies aging and many age-related chronic diseases, which in turn increases the rate of aging [26]. Excess nutrients are an important factor in inflammation, diet performs an important role in the development and treatment of inflammation and related problems, and CR can slow inflammation and improve aging [67]. The activation of innate immune Toll-Like receptors perform an important role in the aging process, and when Toll-like receptors are knocked out, it can significantly ameliorate the aging of heart-related cells [68]. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway plays an important role in regulating inflammatory response, and the inhibition of JAK/STAT signaling pathway can reduce age-related inflammatory response to a certain extent [69].
Innate immunity plays an important role in the aging process. The cytosolic cyclic GMP–AMP synthase (cGAS)-STING pathway is an important signaling pathway in cells whereby cytoplasmic sensory DNA activates immunity (Figure 1) [70]. During aging, cytoplasmic chromatin fragments (CCFs) leaked from the nucleus, and along with micronuclei or DNA that has escaped from the mitochondria, activate the cGAS-STING pathway, and thus facilitate SASP [71]. SASP promotes the senescence of adjacent or circulatory cells via paracrine signaling [72]. Recent studies have found that yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ)-mediated control of cGAS-STING signaling is an important molecular mechanism in the regulation of aging in stromal cells and contractile cells. YAP/TAZ is also important for maintaining nuclear envelope stability via the modulation of Lamin B1 expression [73].

2.6. Circadian Rhythm

The production and maintenance of circadian rhythm is the result of positive and negative feedback loops regulated by a series of genes associated with the biological clock, including BMAL, CLOCK, PER, CRY, REV-ERB-α, ROR-β, etc. [74] (Figure 1). The circadian rhythm/clock genes are closely related to aging and two-way adjustment, with aging leading to the transcriptomic reprogramming of circadian genes. For example, the absence of the core clock transcription factor Bmal1 leads to multiple aging-like pathologies in mice [75]. Disturbances in the circadian rhythm accompany the occurrence of aging, and can contribute to the onset and progression of aging-related neurodegenerative diseases [76]. Notably, Salvador Aznar Benitah group and Sassone-Corsi group by comparing mice of different ages, revealed that a low-calorie diet can improve the circadian rhythm of somatic and stem cells, inhibiting the aging process [77][78].

This entry is adapted from the peer-reviewed paper 10.3390/genes14020329

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