DNA Damage, Transposable Element Expression and Their Associated Factors in Aging

1. Introduction

Aging is a complex, multifaceted process leading to widespread functional decline that affects every organ, tissue, and cell. This also causes deterioration in their structure, function, adaptability, and resistance (Ferrucci et al., 2020). Molecular damage is the primary factor that affects aging and alterations an essential biomolecules in cell. Additionally, molecular damage initiates cellular senescence, which further accelerates the accumulation of intracellular damage (Ogrodnik et al., 2019). The cells, tissues, and organs face various barriers due to the accumulation of molecular damage. The accumulation of molecular damage leads to genome instability (Singh et al., 2019), telomere dysfunction (Zhenshu Li et al., 2022), loss of proteostasis (Bharath et al., 2020), mitochondrial dysfunction (Tracy et al., 2022), stem cell exhaustion (Lei et al., 2022), and epigenetic alterations (Van Der Laan et al., 2022), these factors are the main drivers of the aging. DNA damage and the accumulation of damaged DNA disturbs the stability of cells and lead to genome instability (Kubben et al., 2017). Telomere is repetitive sequences located at the ends of chromosomes and it became critically short during cell division, reaching to the Hayflick limit, finally leads to DNA damage and cellular senescence (Herrmann et al., 2018). When the telomeres become too short after numerous divisions, cell division becomes stops. Then the cell activates genetic programs, such as replicative senescence due to telomere shortening, and the accumulation of senescent cells can accelerate tissue and organism aging (Ovadya et al., 2014). The telomere dysfunction also triggers a DNA damage response, which leads to the expression of proinflammatory factors, ultimately resulting in aging of the organism (Yukun Zhu et al., 2019). Mitochondrial dysfunction is an imbalance mitochondria of network, leading to impaired function and disruption of the metabolic state, which also accelerates aging (Hood et al., 2019). During mitochondrial dysfunction, there is usually a decrease in MMP, which is often accompanied by an increase in reactive oxygen species (ROS) production (Sun et al., 2016). The increase in ROS levels within cells leads to chronic oxidative stress, which in turn disrupts crucial pathways and has an impact on the aging process (Mossad et al., 2022). ROS, or reactive oxygen species, play a significant role in causing cellular damage due to their high reactivity (Yang et al., 2010). According to the Seung-Jae study, small amounts of ROS can promote longevity in C. elegans, whereas high doses have the opposite effect and reduce their lifespan (Seung-Jae Lee et al., 2010). Antioxidant enzymes play a crucial role in neutralizing reactive oxygen species (ROS) and protecting against oxidative stress. When the activity of mitochondrial antioxidant enzymes is impaired, it can lead to an increase in oxidative stress. This was observed by Schriner, in mice lacking dependent superoxide dismutase (SOD) or catalase, which resulted in premature death due to severe mitochondrial dysfunction and neuro-degeneration. On the other hand, mice with a transgene of SOD or catalase showed increased longevity (Schriner et al., 2005). The accumulation of cellular senescence is also another driving force of aging (López-Otín et al., 2013), primarily caused by dysfunction of cellular activity and molecular damage from both internal and external factors (Hernandez-Segura et al., 2018). The cellular senescence affects tissue regeneration by causing an excessive accumulation of senescent cells. Additionally, these cells secrete a large number of inflammatory factors and exhibit the senescence-associated secretory phenotype (SASP), which has detrimental effects on the surrounding environment (Baker et al., 2016).

Transposable elements are found in the genomes of hosts and can impact different aspects of the aging process and various age-related diseases, such as cancer (De Luca et al., 2016, Di Ruocco et al., 2018, Rodić et al., 2014) and Alzheimer's disease (Gao et al., 2018, Wenyan Sun et al., 2018). The activation of these internal transposable elements affects the stability of the genome, resulting in insertional mutagenesis, DNA damage, and rearrangement of the genome (Burns et al., 2012). This review primarily focuses on exploring the causes and effects of molecular damage and cellular dysfunction associated with the process of aging. Specifically, it explores DNA damage, telomere shortening, mitochondrial dysfunction, autophagy dysfunction and cellular senescence. Additionally, it explores the pathways that are affecting the aging process directly. These pathways include the insulin/IGF-1 signaling pathway, the mTOR pathway, Sirtuin 1 (SIRT1), and the AMPK pathway.

2. Molecular Damages and Associated Factors Driving Aging

This review cannot cover all forms and manifestations of molecular damage, but I note the importance of DNA damage and its molecular consequences, such as genome instability, telomere dysfunction, mitochondrial dysfunction, epigenetic alterations, autophagy dysfunction, and cellular senescence.

2.1. DNA Damage and Genome Instability

DNA is highly susceptible to damage from a multitude of exogenous and endogenous factors that encompass any changes in the chemical structure of DNA within cells and influence the process of aging (Curtin, 2012). DNA damage occurs thousands of times each day in every cell, with oxidative damage being a significant cause (Swenberg et al., 2011). Mitochondrial respiration is a primary source of endogenous oxidative DNA damage (Maynard et al., 2009). It’s the driving force behind aging in humans and mammals, through its direct effects of the lesions on DNA replication or transcription, cell elimination or cessation of cell replication, and DNA mutations (Vijg, 2021). The decline in repair capacity of damaged DNA leads to the accumulation of DNA damage. This accumulation, in turn, contributes to cellular senescence and mutations in both nuclear and mitochondrial genes (Sirbu et al., 2013). According to findings, DNA damage accumulation is a pillar of aging (Kennedy et al., 2014) and has a range of molecular consequences such as genome instability, telomere dysfunction, mitochondrial dysfunction, epigenetic alterations, and proteostatic stress (Schumacher et al., 2021). DNA damage is driving of aging, via activating signaling responses (Fagagna et al., 2003), blocking transcription (Vermeij et al., 2016), and mutagenesis (Vijg, 2014). The DNA strand can broke-down by endogenous (from internal biological processes) and exogenous (from the environment). This, in turn, triggers the activation of the DNA damage response (DDR) pathway (López-Otín et al., 2013). The DNA damage response (DDR) involves distinct and universally conserved repair and signaling pathways. These pathways are responsible for detecting specific changes in the DNA, halting the cell cycle, and repairing the damage. When the damage is effectively repaired, the signaling in the DDR is stopped and the cells return to their original, pre-damaged state (Fitsiou et al., 2021). To do that DDR starts with the MRN complex (MRE11-RAD50-NBS1) activating the PIKKs, including ataxia-telangiectasia mutated, ATM-related kinase (ATR), and other related PIKKs (Thompson, 2012). The continuous signaling of DNA damage, which involves the activation of p53 and other response pathways, has both positive and negative consequences. It impacts various aspects of cellular function and plays a crucial role in determining cell fate (Yousefzadeh et al., 2021). When lesions cannot be repaired, the DDR signaling continues, which then leads to either cell senescence or cell death (Fitsiou et al., 2021). However, dysfunction of p53 enables cells to proliferate under unfavourable conditions, thus promoting the growth of cancer cells (Kaiser et al., 2018), disrupt tissue development, in mice exhibit growth retardation or minor developmental abnormalities (Rinon et al., 2011, Tateossian et al., 2015). Defects in DNA repair pathways are associated with specific genome instability syndromes, which are characterized by developmental defects, an increased risk of cancer, and signs of accelerated aging (Menck et al., 2014, Richard D Wood, 2018). Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome are rare genetic disorders in humans that cause premature aging and a shortened lifespan. HGPS and Werner syndrome are caused by mutations in genes that control DNA repair and the A-type lamin, which results in disorganized chromatin structures (Arancio et al., 2014). Thus are associated with genome instability and significantly accelerate aging (Burla et al., 2018). Understanding the molecular pathology of these premature aging diseases also provides insights into the complex aging process. However, individuals with HGPS do not exhibit all the typical signs of aging, as the syndrome primarily affects multiple tissues. Nonetheless, these models allow us to replicate some of the molecular and cellular changes associated with natural aging, giving us a unique opportunity to study the aging process in a human context (Arancio et al., 2014, Burtner et al., 2010). Nestor-Guillermo progeroid syndrome is also another progeroid syndrome, caused by mutations in the BANF1 gene, which accelerating aging due to impaired chromatin organization (Loi et al., 2016). Mutations in the ATM gene, which produces a serine/threonine kinase that becomes active when DNA is damaged, are responsible for causing ataxia telangiectasia (AT), which also exhibits premature aging of the hair and skin (Thompson, 2012, Valentin-Vega et al., 2012). This is indicative of accelerated aging (Rothblum-Oviatt et al., 2016). The helicase encoded by the WRN gene is responsible for managing replication stress and maintaining telomere stability, and mutations of this gene also lead Werner syndrome (WS) (Kudlow et al., 2007). Individuals with WS exhibit symptoms such as growth retardation, premature hair graying, lipodystrophy, and early onset of various age-related diseases (Sugimoto, 2014). Furthermore, Bloom syndrome (BS) is also caused by mutations in the BLM gene, which encodes a RecQ helicase that plays a crucial role in suppressing recombination and maintaining genome stability (Nguyen et al., 2014). Individuals with BS have an average lifespan of 26 years and experience premature onset of numerous age-related diseases, including cancer, diabetes, and chronic obstructive pulmonary disease (De Renty et al., 2017).

2.2. Telomer Shorting

Telomeres are repeating, noncoding DNA sequences located at the ends of eukaryotic chromosomes, primarily composed of telomeric DNA and telomere-binding proteins (Maciejowski et al., 2017). In mammals, it’s made up of thousands of TTAGGG repeats. These repeats are covered by sheltering complex, which helps create a T-loop structure that hides the end of the telomere. This hiding mechanism prevents the activation of DDR sensors (De Lange, 2018). Telomeric DNA becomes shorter as cells divide more, and when it reaches the Hayflick limit, dysfunction of the telomeres triggers the response DNA damage. As a result, cells stop dividing and start expressing proinflammatory factors, leading to aging in the organism (Yukun Zhu et al., 2019). The length of telomeres is regulated by telomerase, when telomerase activity is increased and the chromosomes remain intact, the lifespan of an organism is extended (Yukun Zhu et al., 2019). However, telomerase becomes inactive, the length of telomeric ends is blocked in somatic human cells, and telomeres become shorter with each successful cell division, leading to restricted cell proliferation. This process is known as replicative senescence (Ishikawa, 2013). During replicative senescence, irreparable DNA damage is accumulated, leading to permanent cell-cycle arrest and is considered one of the main factors driving aging (Günes et al., 2013). Herrmann's and Jiang-Yi findings confirmed that mice without telomerase have shorter telomeres and experience premature aging. Conversely, mice that are resistant to cancer and have high levels of telomerase expression have longer telomeres and age at a slower rate (Herrmann et al., 2018, Jiang-Yi Wang et al., 2017). The telomere without protection appears similar to a DNA double-strand break (DSB), causing the continuous activation of DDR, which ultimately results in replicative senescence (Fumagalli et al., 2012). One mechanism currently being studied as a significant contributor to telomeres length attrition is cellular oxidative stress (Monaghan et al., 2018). This occurs when the concentration of pro-oxidant molecules in the body is higher compared to that of antioxidant substances (Halliwell et al., 2015). Telomere is highly susceptible to oxidative damage due to the presence of numerous guanine triplet sequences. These sequences are more prone to oxidation when compared to other bases (Von Zglinicki, 2002). Increased levels of glucocorticoid hormones (GC) can also cause telomeres to attrition in vertebrates, including humans (Angelier et al., 2018, Haussmann et al., 2015). This occurs because GC hormones increase cellular oxidative stress by reducing natural antioxidant defences (Angelier et al., 2018, Costantini et al., 2011) and suppressing telomerase expression (Choi et al., 2008). Another important signaling pathway that causes telomere attrition is NAD⁺-SIRT1-PGC-1α axis. In this axis, short telomeres are recognized as double-strand breaks by NAD⁺ dependent peroxisome proliferator-activated receptors (PARP1), which can initiate DNA repair signals, a process that requires the consumption of NAD⁺. Hyper-activation of peroxisome proliferator-activated receptors 1 (PARP1) leads to NAD⁺ consumption, hence limiting NAD⁺-dependent deacetylase sirtuin-1 (SIRT1) activity (Fang et al., 2014, Gibson et al., 2012). SIRT1 has been revealed to increase mitochondrial function and biogenesis through the transcription factor PGC-1α. Loss of SIRT1 activity therefore leads to mitochondrial dysfunction (Fang et al., 2014) lead to increase ROS production. ROS is also other main cause of telomere attrition (Gonzales-Ebsen et al., 2017). ROS can generate approximately 100 different types of oxidatively damaged bases (Cadet et al., 2013). The length of telomeres is also attributed by Ku-proteins, which are regulated by TOR through two pathways. First, when Ku-proteins are present, they directly interact with telomeric repeats to increase telomerase expression. This, in turn, promotes telomere length (TL) maintenance (Pfeiffer et al., 2012). Conversely, inhibiting TOR leads to a decrease in Ku-protein expression, resulting in reduced telomerase expression and TL attrition. Second, Ku-proteins can also bind to telomeric RNA repeats called TERRA (Telomeric Repeats containing RNA with repetitive UUAGGG sequences (Arnoult et al., 2012)). When Ku-proteins bind to TERRA, they can induce TL shortening by promoting the expression of the enzyme Exonuclease I. This enzyme cleaves nucleotides from telomeric DNA (Pfeiffer et al., 2012).

2.3. Epigenetic Alterations

Epigenetic mechanisms encompass various processes, such as DNA methylation, histone modifications, chromatin remodeling, and transcriptional alteration through noncoding RNAs (ncRNAs) (Sen et al., 2016). The first epigenetic alteration is DNA methylation, which occurs directly at the DNA level. It regulates gene expression by interacting with the proteins involved in gene silencing or inhibiting the interaction between DNA and transcription factors (Nikolac Perkovic et al., 2021). DNA methylation has various functions, including the alternative splicing, and the regulation of gene expression (Moore et al., 2013). The DNA methyltransferases (DNMTs) are enzymes that play a role in DNA methylation, to transfer a methyl group at the fifth position of cytosine (5mC) from S-adenosyl-methionine (SAM) to the carbon-5 position of the cytosine residues in the CpG region (Hervouet et al., 2018, Jeltsch et al., 2017). 5-Hydroxymethylcytosine (5hmC) is a modification of DNA base that is derived from 5-methylcytosine through the actions of the ten-eleven translocation protein family (Zarakowska et al., 2018). A recent study has found that the deamination of 5mC and oxidative damage are significant factors in somatic mutagenesis (Cagan et al., 2022). These mutations also lead to the development of cancer (Stratton et al., 2009), leads to premature aging, specifically Werner's syndrome and Hutchinson-Gilford Progeria syndrome (Horvath, 2013) and those are highly contribute to ageing (Vijg et al., 2020). Histone modifications are a type of epigenetic alteration, including acetylation, methylation, phosphorylation, ubiquitination, and glycosylation. Among these, acetylation and methylation are the most characteristic modifications associated with senescence (Paluvai et al., 2020). When histone methyltransferases or histone demethylases are present, they can alter the levels of histone methylation, which can then participate in either transcriptional activation or repression. Generally, methylation at lysine 4 of histone 3 (H3K4), H3K36, and H3K79 promotes transcriptional activation, while methylation at H3K27 and H4K20 causes transcriptional repression (Yi et al., 2020). Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are enzymes that catalyse histone acetylation or deacetylation reactions. HATs are typically involved in activating transcription, while HDACs exert repressive (Yuan Wang et al., 2018). These enzymes are crucial for longevity, as demonstrated by studies on yeast (Kirfel et al., 2020). In particular, when the histone acetyltransferase gene GCN5 is deleted, it leads to a decrease in the replicative lifespan of yeast (Yuan Wang et al., 2018). H3K36me3 and H3K9me3 also have important roles in the aging process. In both S. cerevisiae and C. elegans, a deficiency in H3K36me3 is associated with a shorter lifespan. Consistently, the lifespan of S. cerevisiae is extended when there is a loss of H3K36me3 demethylase (Sen et al., 2015). Similarly, the loss of H3K9me3 in the adult Drosophila midgut leads to aging of intestinal stem cells (Jeon et al., 2018). Interestingly, in aged somatic tissues of C. elegans, there is an increase in global H3K9me3 levels at heterochromatic regions in the distal arms of chromosomes, but a decrease in euchromatic central regions of autosomes (Cheng-Lin Li et al., 2021). According to Jason's findings, in Drosophila, the signals for H3K9me3 and Heterochromatin protein 1 (HP1) on chromosomes are significantly higher in young flies but not in aged flies. Additionally, overexpression of HP1 reduces premature aging and extends lifespan (Jason G Wood et al., 2010). Furthermore, diminished levels of H3K9me3 and HP1 in mesenchymal stem cells (MSCs) carrying pathogenic mutations of HGPS or Werner Syndrome (WS), which also accelerate aging (Zunpeng Liu et al., 2022, Wu et al., 2018, Weiqi Zhang et al., 2015). The third epigenetic alteration is chromatin remodelling, which modifies chromatin structure and the position of nucleosomes using ATP-dependent enzyme similar to helicase. This allows regulatory proteins to interact with DNA. Liu et al. discovered that the Switch/sucrose non-fermentable (SWI2/SNF2) complex's core structural domain connects to each other through two induced Brace helices. This anchors chromatin remodelers to specific nucleosome positions and initiates substrate for remodelling reactions (Xiaoyu Liu et al., 2017). During senescence-induced mitochondrial stress, a malfunction in the tricarboxylic acid cycle results in reduced production of acetyl coenzyme (acetyl-CoA). This reduction leads to the accumulation of histone deacetylase and homeobox protein dve-1 in the nucleus, causing a decrease in histone acetylation and chromatin reorganization in C. elegans. On the other hand, the addition of nutrients that enhance acetyl-CoA production is enough to delay the lifespan of C. elegans following mitochondrial stress (Di Zhu et al., 2020).

2.4. Mitochondrial Dysfunction

The main factor behind mitochondrial dysfunction is often attributed to damage induced by reactive oxygen species (ROS) to the mitochondrial genome (Kauppila et al., 2017). During mitochondrial dysfunction, the mitochondrial membrane potential (MMP) decreases and is associated with increased production of reactive oxygen species (ROS) (Sun et al., 2016) and indicate ETC dysfunction (Nacarelli et al., 2019). About 90% of ROS is produced in mitochondria from a leakage of electrons in the electron transport chain (Gruber et al., 2013). Increased production of reactive oxygen species (ROS) can cause oxidative damage to mitochondrial DNA, proteins, and lipids. This damage, in turn, reduces mitochondrial dynamics and hinders mitophagy, ultimately leading to mitochondrial dysfunction (Bakula et al., 2020). Mitochondrial dysfunction has been also associated to aging and various age-related diseases, such as cancer, neurodegenerative, kidney diseases (Sun et al., 2016, Zhunina et al., 2021). During mitochondrial dysfunction, MMP is reduced (Bagkos et al., 2014) and increased production of reactive oxygen species (ROS) are also stress-induced senescence (Passos et al., 2010), replicative senescence, oncogene-induced senescence (Nelson et al., 2018), and senescence triggered by genetic telomere uncapping (Passos et al., 2010). The defective of proofreading activity of mtDNA polymerase contributes to mtDNA mutations, which in turn cause significant mitochondrial dysfunction and premature aging (Trifunovic et al., 2005). High levels of reactive oxygen species (ROS) and mutations or deletions in mitochondrial DNA (mtDNA) can result in a defective proofreading activity of mtDNA polymerase. This, in turn, leads to damage in the replication system and/or repair mechanisms of mtDNA (Ryzhkova et al., 2018). According to Vermulst et al., findings, the deletions of mtDNA are drivers of premature aging in mice (Vermulst et al., 2008) and also induce cellular senescence (Kolesar et al., 2014). Moreover, mitochondrial dysfunction also associated with chronic inflammation in different diseases, such as myocardial infarction (MI), sickle cell disease, and neurodegenerative disorders (De Oliveira et al., 2021, Marchi et al., 2023) and it also caused dysregulated nutrient sensing pathways, such as insulin/IGF-1, mTOR, AMPK, and sirtuins (Bartolomé et al., 2017).

2.5. Autophagy Alterations

Autophagy is a well-conserved process that breaks down cellular components, such as damaged organelles and misfolded protein aggregates (Dikic et al., 2018), within lysosomes. Under normal conditions, autophagy is regulates by ROS, but excessive ROS can damage organelles and cause protein modification and aggregation. On the other hand, autophagy can mitigate oxidative damage (Jisun Lee et al., 2012). During starvation, ROS-induced activation of AMPK induced autophagy. In cells deficient in ETC, O₂⁻ production is halted under starvation conditions, which decreases AMPK activation and increases activation of the mTOR pathway. Consequently, starvation-induced autophagy is reduced (Lin Li et al., 2013). Downstream of AMPK, peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) is essential for modulating antioxidant genes in response to oxidative stress. The AMPK-PGC-1α signaling pathway controls mitochondrial ROS levels. Cells with decreased AMPK activity experience elevated mitochondrial ROS and undergo premature aging (Rabinovitch et al., 2017). Dysfunction of autophagy via various factors significantly speeds up the aging process in different species (Aman et al., 2021). However, increase the autophagy activity can slow down aging (Leidal et al., 2018). According to Aman et al., study the increased expression of autophagy genes ATG-1, ATG-7, and ATG-18 in C. elegans leads to an extended lifespan (Aman et al., 2021). Autophagy also has a crucial role in clearing damaged mitochondria, which means that when autophagy is compromised, it leads to mitochondrial dysfunction, abnormal mitochondrial accumulation, and oxidative stress (Hansen et al., 2018, Jisun Lee et al., 2012). The decline in repair capacity of DNA due to various factor leads to the accumulation of DNA damage. This accumulation, in turn, contributes to cellular senescence and mutations in both nuclear and mitochondrial genes, which have been associated with aging (Sirbu et al., 2013). One of the main causes of impaired DNA repair mechanism is that the defect in autophagy (Hewitt et al., 2017). According to the findings of Yanan and his colleagues, the accumulation of p62 has been observed in rats when autophagy is dysfunction, which in turn disturbs DNA damage responses (DDR) (Yanan Wang et al., 2016). However, inhibiting p62 accumulation also reduces defective autophagy-induced genome damage (Mathew et al., 2009). Usually p62 is involved in regulating the balance between NHEJ and HR (Hewitt et al., 2016). Under autophagic deficiency (Atg3 knockout), the recruitment of DNA repair proteins such as BRCA1, RAP80, and Rad51 to double strand breaks is compromised in a p62-dependent manner (Yanan Wang et al., 2016). Autophagy-deficient cells have defective activation of checkpoint kinase-1 (Chk1), which is important for DNA repair through HR. The failure of Chk1 in response to DNA damage results in reduced recruitment of Rad51 to the damaged sites (Gillespie et al., 2016). In Atg5-deficient embryonic fibroblast cells, the deficiency in autophagy leads to the failure to sense damaged DNA by XP group C (XPC) and DNA damaging-binding protein 2 (DDB2) (Qiang et al., 2016). Moreover, impaired autophagy results in DNA damage, increased mutation rates, and chromosomal instability in different cell (MEFs) (Mathew et al., 2007).

3. Cellular Senescence

Cellular senescence is a state of irreversible cell cycle arrest (Morsli et al., 2022). Aging results in both biological and functional changes, affecting not only organism but also cellular level (Hansen et al., 2018). The senescent cells constantly secrete SASP factors, including proinflammatory cytokines, chemokines, growth factors, and proteases, which alter the local tissue environment and contribute to aging and aging-related disorders (Ohtani, 2022). Immune cells can aggravate the progression of aging-related diseases by triggering the production of more proinflammatory cytokines (Zhou et al., 2021). Additionally, T-cell senescence is considered a key aspect of immune senescence. Premature T-cell accelerate aging in various organs and systems, with thymic degeneration, mitochondrial dysfunction, genetic and epigenetic changes, and protein homeostasis imbalance being the primary indicators of T-cell senescence (Mittelbrunn et al., 2021). Desdín-Micó G et al. discovered that mice lacking mitochondrial transcription factor A (TFAM) experienced a range of aging-related symptoms, due to T cells senescence with mitochondrial dysfunction and ultimately, led to accelerating aging and premature death in the mice (Desdín-Micó et al., 2020). In other cause, DNA repair systems fail, cellular damage occurs, contributing to the cellular and organism aging. Several factors, such as oxidative stress, DNA damage, telomere shortening, and the senescence-associated secretory phenotype (SASP) of inflammation, may play key roles in trigger aging (Henriques et al., 2012, Yu Sun et al., 2018). Oxidative stress is primarily caused by reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radicals. This stress can lead to DNA, lipid, and protein damage, ultimately resulting in cellular aging (Indo et al., 2015). The main antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), peroxidase (GPX), and glutathione (GSH), work to reduce excessive ROS, however, their effectiveness is reduced by cellular aging and leads to rise ROS level (Balaban et al., 2005). The senescent state is regulated by the p53/p21 and p16/pRB pathways (Abbas et al., 2017, Campisi, 2013, Muñoz-Espín et al., 2014). When there is DNA damage, the p53 pathway is activated, leading to the expression of p21, which is an inhibitor of cyclin-dependent kinase (CDK), as a result the retinoblastoma protein (pRB) becomes activated (Lanigan et al., 2011, Muñoz-Espín et al., 2014). Hence, pRB also plays a crucial role in senescence by binding and deactivating the E2F family of transcription factors, which are responsible for inducing cell cycle proteins and DNA replication factors. This establishes a reciprocal regulation between the p53/p21 and p16/pRB signalling pathways. However, these pathways can independently induce senescence (Lanigan et al., 2011). Cellular senescence mainly triggered by DNA damaging (Di Micco et al., 2021). If DNA damage cannot be repaired and continues, results in prolonged DDR signaling and long-term proliferation arrest in the form of cellular senescence (Fumagalli et al., 2014). Based on various findings, another primary causes of cellular senescence are telomere shortening (Bernadotte et al., 2016), mitochondrial dysfunction (Wiley et al., 2016, Yue et al., 2016) and the dysfunction of autophagy pathways (Gewirtz, 2013). The p53 function loss promotes chromosomal instability and causes cellular senescence or apoptosis (Qianqian He et al., 2018). Cellular senescence is crucial in preventing the formation of tumors, aiding in tissue repair and wound healing, promoting insulin secretion, and supporting mammalian development (Demaria et al., 2014, Helman et al., 2016, Storer et al., 2013). However, the accumulation of senescent in the cells over time, likely due to decreased immune-clearance in almost all vertebrates (Yan Liu et al., 2009) and has been proven to actively contribute to the process of aging (Roos et al., 2016). Senescent cells also play a role in age-related diseases like atherosclerosis (Roos et al., 2016), osteoporosis (Chandra et al., 2020), non-alcoholic fatty liver disease (Ogrodnik et al., 2017), cancer (Alimirah et al., 2020), neurodegenerative diseases (Chinta et al., 2018, Peisu Zhang et al., 2019), and other conditions associated with aging (Kirkland et al., 2020).

4. Conserved Genetic Pathways

The process of aging and the frequency and severity of age-related diseases are affected by different conserved genetic pathways. These important pathways include the insulin/IGF-1 signaling pathway, the mTOR pathway, and the AMPK pathway (López-Otín et al., 2013). When cellular nutrients are abundant, the insulin/IGF-1 and mTOR pathways are activated, leading to the promotion of anabolic processes and the inhibition of autophagy (Johnson, 2018). In mammals, insulin/IGF-1 signaling plays a crucial role in coordinating nutrient availability with energy balance and metabolic processes. This signaling pathway is activated by insulin-like peptide ligands in response to nutrient availability. One way that insulin/IGF-1 signaling transmits signals is through the PI3K/Akt pathway, which phosphorylates various targets, including tuberous sclerosis complex (TSC1/2) (Templeman et al., 2018). The insulin/IGF-1 signaling (IIS) pathway is a crucial mechanism that controls ageing in eukaryotes. Extensive evidence supports the idea that reducing IIS promotes longevity and enhances overall health in various species, such as nematodes, flies, and mice (Johnson et al., 2013). Insulin/IGF-1 also controls protein synthesis, energy metabolism, and the proliferation and differentiation of insulin/IGF-1 sensitive cells. According to Bartke finding, the defects of insulin/IGF-1 signaling pathway extend longevity’s, however over activating of pathway accelerates the aging (Bartke et al., 2013). Furthermore, Ock's study also revealed that removing IGF-1R in mouse cardiomyocytes reduced age-related myocardial inflammation, hypertrophy, and interstitial fibrosis in the heart. This suggests that the opposing effects of insulin/IGF-1 signaling have significant impacts on the overall health and lifespan of mammals (Ock et al., 2016). mTOR is a serine/threonine kinase that belongs to the phosphoinositide kinase-related family, and has mTOR 1 and mTOR 2 complex. Activation of mTORC1 occurs through phosphoinositide-3-(PI3)-kinase-related kinase family and AKT kinase signaling, as well as by nutrients like amino acids and phosphates (Laplante et al., 2012). Activated TORC1 promotes anabolic processes, such as protein, lipid, and nucleotide synthesis, while inhibiting catabolic processes like autophagy (González et al., 2017). The frequent alteration of mTOR plays an important role during tumorigenesis, metastasis, and drug resistance in human malignancies (Yundong He et al., 2022, Kirtonia et al., 2022). In senescence, mTOR is persistently activated (Carroll et al., 2017), possibly due to increased levels of reactive oxygen species (ROS) produced by dysfunctional mitochondria (Nacarelli et al., 2016). The dysregulation of mTOR function can lead to the development of neurodegenerative diseases, which are characterized by the aggregation of proteins (Perluigi et al., 2015). The AMPK pathway, which is the third important pathway discussed in this review, its activated when cellular energy levels decrease and when there are high ratios of AMP/ATP and ADP/ATP (Lin et al., 2018). AMPK is responsible for regulating homeostasis, metabolism, stress resistance, cell survival and growth, cell death, and autophagy. These factors play a crucial role in determining the aging process and lifespan (Salminen et al., 2012). The activation of AMPK encourages the formation of new mitochondria and regulates their dynamics and mitophagy (Toyama et al., 2016). According to recent findings, the activation of AMPK increases the lifespan of D. melanogaster by 30%, extending it from six weeks to eight weeks (Moqrich, 2014). On the other hand, AMPK activation is induced by caloric restriction protects rats against senescence by enhancing autophagic activity and reducing oxidative damage (Ning et al., 2013). AMPK also plays a crucial role in autophagy (Salminen et al., 2012), which is a cellular degradation pathway that breaks down and reuses components to maintain cellular balance (Ma et al., 2018). Dysfunction of autophagy is strongly associated with ageing and organ dysfunction (García-Prat et al., 2016). The dysregulation of AMPK is associated with accelerated aging due to promoting inflammation, cancer, and metabolic pathologies such as diabetes and obesity (Garcia et al., 2017). Another important pathway is Sirtuins play a crucial role in regulating a wide range of cellular processes, including metabolism, mitochondrial homeostasis, autophagy, DNA repair, apoptosis, oxidative/antioxidative balance, and senescence . The main mechanisms by which Sirtuin suppresses cellular senescence involve delaying age-related telomere attrition, maintaining genome integrity, and promoting DNA damage repair. SIRT1 also enhances the ability to induce cell cycle arrest and oxidative stress resistance, while inhibiting cell death (Brunet et al., 2004) and apoptotic pathways (Yanfei Liu et al., 2019). Similarly, SIRT1 is implicated in a range of age-related processes and disorders, including neurodegenerative diseases and cardiovascular diseases (Zhao et al., 2020). Subsequent studies have shown that sirtuins can regulate longevity in various lower organisms, particularly yeast Sir2 and its homologues, which extend lifespan in budding yeast S. cerevisiae, worms, C. elegans, fruit flies, D. melanogaster, and mice (Kanfi et al., 2012, Kapahi et al., 2017). The pro-longevity effect of Sir2 also confirmed in higher organisms, although the mechanisms of its pro-longevity effects differ from those in yeast. These mechanisms include changes in mitochondrial function and biogenesis, suppression of inflammation, and regulation of genomic stability (Wątroba et al., 2016). The dysregulation of insulin/IGF-1, mTOR, AMPK, and other conserved signaling pathways closely associated with human aging and age-related diseases resulting from inadequate nutrient supply (Fernandes et al., 2021, Johnson, 2018).

5. Transposable Elements

TEs are DNA sequences that can move within genomes without the help of host cell DNA. TEs constitute about 50% of the human genome (Jönsson et al., 2020) and 85% of plants genome (Wicker et al., 2018). Reducing DNA methylation and loss of heterochromatin are highly contributed to the rapid increase of TE expression and transposition (Sedivy et al., 2013). The activation of endogenous transposable elements greatly causes to genome instability (Burns et al., 2012), telomere dysfunction, mitochondrial dysfunction, epigenetic alterations, and proteostatic stress (Schumacher et al., 2021). Several studies have indicated that overexpression of TE is associated with an increase in immune response and inflammation (De Cubas et al., 2020, Ching-Hsuan Liu et al., 2020) because transposable elements have the ability to be translated into proteins and peptides. When these peptides are present in the cell membrane, they are recognized as foreign elements, triggering an innate immune response. As a result, the induction of innate immunity leads to an increased expression of pro-inflammatory factors such as IFN and cytokines, which in turn further promotes TE expression. This positive feedback loop of TE overexpression consequently leads to an enhanced expression of inflammatory factors (Ochirov, 2019, Römer, 2021). Additionally, the expression and translation of transposable elements can also result in the formation of toxic products. These products, for instance, can contribute to the development of autoimmune diseases. Furthermore, the activity and replication of TEs within an increased genomic TE content may indirectly impose metabolic costs on the host (Bogu et al., 2019, Volkman et al., 2014). Altered activity of specific transposable elements is also associated with multiple age-associated pathologies, including cancer (Di Ruocco et al., 2018) and Alzheimer's disease (AD) (Gao et al., 2018). The activation of TEs and its connection to aging is supported by a study conducted in termites. This study reveals that reproducing queens and kings can live for decades without a substantial rise in TE expression levels. On the other hand, major workers, with a lifespan of only a few weeks, exhibit an up-regulation of TEs as they age (Elsner et al., 2018). Recent studies have shown that both calorie restriction (CR) and anti-aging drugs like rapamycin can decrease TE transcript levels, while aging and age-accelerating interventions can also increase TE expression (Wahl et al., 2021). In addition to using anti-aging agents, the lifespan of mutant flies or mice with overexpression of TEs can be extended through the use of nucleoside reverse transcriptase inhibitors (NRTIs), which suppress TE reverse transcriptase (Gorbunova et al., 2021).