Molecular Signaling and Clinical Implications in the Human Aging-cancer Cycle

Abstract

It is well documented that aging is associated with cancer, and likewise, cancer survivors display accelerated aging. As the number of aging individuals and cancer survivors continues to grow, it raises additional concerns across society. Therefore, unraveling the molecular mechanisms of aging in tissues is essential to developing effective therapies to fight the aging and cancer diseases in cancer survivors and cancer patients. Indeed, cellular senescence is a critical response, or a natural barrier to suppress the transition of normal cells into cancer cells, however, hypoxia which is physiologically required to maintain the stem cell niche, is increased by aging and inhibits senescence in tissues. Interestingly, oxygen restriction or hypoxia increases longevity and slows the aging process in humans, but hypoxia can also drive angiogenesis to facilitate cancer progression. In addition, cancer treatment is considered as one of the major reasons that drive cellular senescence, subsequently followed by accelerated aging. Several clinical trials have recently evaluated inhibitors to eliminate senescent cells. However, some mechanisms of aging typically can also block cancer cell growth and progression, which might require careful strategy for better clinical outcomes. Here we describe the molecular regulation of aging and cancer in crosstalk with DNA damage and hypoxia signaling pathways in cancer patients and cancer survivors. We also update several therapeutic strategies that might be critical in reversing the cancer treatment-associated aging process.

Introduction

According to the National Cancer Institute, the rate of cancer incidence steadily grows as age increases. One-fourth of cancer incidence occurs in children and adolescents (individuals under the age of 20). 12% of brain cancers are diagnosed in this age group, which comprises 1% of cancer overall. Despite the increasing rate of cancer incidence, the advances in cancer diagnosis and therapies have also significantly increased to extend the overall survival of cancer patients. According to the American Cancer Society in 2019, 70% of cancer survivors are alive for around 5 years, while 18% survive more than 20 years. The growing population of cancer survivors is estimated to be more than 22 million by 2030. Raising the population of cancer survivors is also associated with increasing aging in many individuals, suggesting that cancers and following cancer treatments might accelerate aging. Cancer survivors can develop age-related diseases with significant morbidity, mortality, and health costs¹. It has been shown that cancer survivors have poor lifespans and age faster, thereby dying sooner than those who have never had cancer^2,3. Therefore, survivors of early-life cancer likely show accelerated aging with elevated age-associated diseases, and premature death⁴. For example, two of seven childhood cancer survivors develop serious chorionic diseases leading to disability or fetal disease⁵. The frequency of a chronic health condition in cancer survivors is 73.4%⁶, and the incidence of second malignancy is likely 8%⁷ with 30% of the probability of survival⁸. However, the molecular mechanisms by which aging is associated with cancer or treatment are likely multifactorial and remain to be further clarified (National Institute of Aging).

The mechanism of the accelerated aging might be due in part to the onset of cellular senescence and/or the type of cancer treatments that induce cellular senescence in normal and tumor cells, leading to the onset of several chronic diseases⁹. It is known that aging is associated with familial factors and host genome and tissue susceptibility to cancer^10,11, which are normally increased upon aging, and more favorable for the growth of cancer cells for progression and metastases¹⁰. Therefore, cancer and aging likely share several hallmarks that might accelerate aging¹². Despite this, many cancer survivors have been exposed to chemotherapy, radiotherapy, immunotherapy, or combination therapies that might damage normal cells to accelerate biological aging processes¹³. Indeed, multiple molecular and cellular mechanisms such as epigenetic alterations, genomic instability, telomere attrition, stem cell exhaustion, and cellular senescence, may drive biological aging¹⁴ in which cancer therapy accelerates this early onset of aging in cancer survivors¹⁵. Interestingly, aerobic exercise maintains genomic stability by activating DNA repair¹⁶. Here we review the cellular and molecular mechanisms involved in accelerating aging. We also discuss possible clinical implications for managing the aging phenomenon in cancer survivors.

Common molecular mechanisms in human aging and cancer

Senescence

Cellular senescence is known as an irreversible arrest of the cell cycle and a cease of cell proliferation in response to intrinsic and extrinsic stimuli^17,18. Senescence is affected by many cellular stimuli including mitochondrial dysfunction, oncogenic activation, oxidative or genotoxic stress, irradiation, and chemotherapeutic effects¹⁹. Indeed, primary cells can survive for a longer time before arresting^17,18. These senescent cells metabolically remained active and displayed physiological and morphological changes (enlarged and flattened shape) with disrupted nuclear envelope integrity, in part due to a reduction in the expression of lamin B1. More importantly, the senescence-associated secretory phenotype (SASP) is characterized in senescent cells by the expression and secretion of growth factors, proinflammatory cytokines, and chemokines such as IL-6 and IL-8^20,21. Senescent cells undergo many changes in tissue microenvironment including chromatin alterations, metabolic changes, and resistance to apoptosis²². Herein, senescent cells have a unique “secretome” compared to non-senescent cells, resulting in cellular inflammation, which can either promote or prevent tumorigenesis of pre-malignant cells in the tumor microenvironment²³. Senescence-associated β-galactosidase (SA-β-gal) is commonly used as a senescent marker²⁴. Moreover, the expression of cell cycle suppressors including p53, p14^ARF, p16^INK4, and p21^CIP1 is an indicator of cell growth arrest and senescence²⁵. Of note, activation of cyclin-dependent kinase inhibitors (p21, p27, and p16) is a critical event in cell cycling. Mechanistically, the p53 tumor suppressor activates p21 to bind and inhibit cyclin-CDK complexes, leading to the hyperphosphorylation of the RB protein and inhibition of cell cycle progression^26,27. The DNA damage response is also identified in senescent cells by the expression and formation of γH2AX foci within telomeric DNA²⁸ (Figure 1). In addition, chromatin reorganization and the formation of senescence-associated heterochromatin foci (SAHF) are also observed in cells undergoing oncogene-induced senescence, which can be recognized by the elevated expression of heterochromatin protein 1 (HP1), macroH2A, and lysine 9 di-or-tri-methylated histone H3 (H3K9Me2/3)²⁹.

Figure 1. Common molecular mechanisms in human aging and cancer.

Cellular senescence is induced by multiple physiological (e.g. telomere attrition, oncogenic activities) and pathological (UV, IR, chemotherapy) stimuli signals, resulting in proliferation, inflammation, invasion, angiogenesis, lysosomal activity, and cell cycle arrest. These upstream stimulators drive several numbers of intracellular signaling pathways including the components of DNA damage response (ATR, ATM, and p53). ATM and ATR are activated by auto-phosphorylation in response to the DNA damage and phosphorylates histone H2AX at S139 for activation of DNA damage repair. The activation of cyclin-dependent kinase inhibitors (p21, p27, and p16), leads to hyperphosphorylation of RB protein. To this end, p21 binds and inhibits cyclin-CDK2, cyclin-CDK1, and cyclin-CDK4,6 complexes, leading to the inhibition of cell cycle progression during G1 and S phases. The oncogenic activity of the Ras-RAF signaling also positively regulates the PI3K-mTORC1 signaling pathway, in which TSC2 can be phosphorylated by AMPK in response to energy stress to inhibit mTORC1 in the aging process²⁵⁶. Moreover, cellular senescence can result from the loss of the function of tumor suppressor genes, leading to mitochondrial dysfunction and the elevation of reactive oxygen species which in turn, elevates cellular DNA damage. Lastly, the secretome of senescent cells is upregulated, which is termed the senescence-associated secretory phenotype (SASP), leading to the release of several proinflammatory cytokines (IL-6, IL-1β, TMF1a, MMP3, and CXCL10) into the surrounding tissue microenvironment for accelerating aging. Positive regulation of the target proteins is shown as an arrow and negative regulation of the substrate protein is shown as a blunt-ended line. ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related.

It is shown that chemotherapy and immunotherapy not only induce cellular senescence in tumor cells but also stimulate senescence in adjacent normal tissues³⁰, leading to accelerated aging^31,32. Moreover, chemotherapeutic agents induce DNA damage to trigger apoptosis in cells and also shorten telomeres to induce replicative senescence³³. For example, doxorubicin can induce senescent markers such as SA-β-gal and p16^INK4 or p21/p53 in several normal and cancer cell lines³⁴. In addition, treatment with cyclophosphamide, 5-fluorouracil, and Adriamycin can also increase SA-β-gal expression in human breast cancer cells³⁵. Radiotherapy also induces ROS production that causes DNA damage and drives cells into either apoptosis or senescence, depending on the degree of DNA damage. Since ionizing radiation (IR) is used in breast cancer, neuroblastoma, fibrosarcoma, and colon cancer it induces p21, p16^INK4, p53, and SA-βgal, which are usually considered as the readouts of the senescent marker³⁵.

DNA damage

It seems that the accumulation of mutations occurs in the specific tissues with high proliferative capacity³⁶, thereby driving more cancer incidence. However, more studies reveal that the efficacy of DNA repair responses is reduced with age through yet unknown mechanisms^37,38. There are several DNA-repair pathways existed³⁹, which we briefly introduce some of them. For example, disruption in the DNA repair signaling such as nucleotide excision repair (NER), promotes premature aging for tumorigenesis⁴⁰. Of note, NER and base excision or mismatch repair (MMR) are two global genome repair mechanisms^41,42. When the DNA repair mechanisms fail, the apoptotic pathway or senescence program is activated to eliminate cells with risky mutations that have the potential for cell transformation into tumors. For example, Progeroid syndromes often originate from mutations and or disruptions in DNA damage responses, leading to an increased level of cancer incidence¹⁰. Long exposure to endogenous (e.g., free radicals) and or exogenous (e.g., ionizing and ultraviolet radiations, chemical agents, and viruses) factors can induce oxidative stress, genomic instability, and finally DNA damage^12,14,43. Reactive oxygen (ROS) and or nitrogen (Nr) species can react with DNA, leading to DNA damage such as oxidation of DNA bases, single strands, and or double-strand breaks^41,42. By the way, DNA repair mechanisms are initiated to arrest the cell cycle to provide a time window for cells to repair and restore DNA damage^41,42.

Non-homologous end joining (NHEJ), is the other major DNA-repair signaling pathway in which the broken DNA strand is ligated without using a homologous template⁴⁴. The NHEJ repair is initiated by Ku70 and Ku80 heterodimer proteins to recognize and recruit other DNA repair components including but not limited to DNA-PKcs, XRCC4, LIG4, XLF, and APLF⁴⁵. In the alternative (alt)-NHEJ, the MRN complex recruits PARP1, and POLQ perform the repair, whereas XRCC1 and LIG1/3 execute the excision and ligation event^46,47. This signaling pathway is also activated when the ends of ssDNA are degraded by endonucleases. Next, the ends are coated with RPA protein and replaced by RAD51 to find the area of homology in the template DNA. One other key player in DNA damage response is ataxia-telangiectasia mutated (ATM), which is recruited by the MRN complex (MRE11-RAD50-NSB1) as a DNA damage sensor to double-strand break. Another main player in DNA damage response is ataxia-telangictasia-Rad3-related (ATR), which is induced after a single-strand break sensed by RPA, ATRIP, and or the RAD6-RAD1-HUS1 complex. ATM and ATR along with DNA-PKcs are a member of the PI3K-related kinase family, which are well-known players in repairing DNA double-strand break through the NHEJ pathway⁴⁸. They might phosphorylate and activate several DNA damage regulators, such as breast cancer gene 1 (BRCA1) and downstream kinases like checkpoint kinases (CHK) 1 and 2, for initiation of DNA repairing which is followed by harboring effectors like P53, to initiate either apoptosis, cell cycle arrest or DNA repair signaling^49,50. Therefore, the accumulation of cellular damage can be a critical driver of the aging process (Figure 2).

Figure 2. Base excision repair and the homologous recombination pathways in response to DNA damage.

Exogenous and endogenous stress triggers DNA damage in the cells for activation of DNA repair signaling pathways. For example, ultraviolet (UV) and the production of ROS resulting from cellular metabolism can directly cause single-strand breaks (SSBs) (left), whereas chemicals and drugs can indirectly induce replication or transcription stress (right). Moreover, irradiation (IR) leads to double-strand breaks (DSBs) for activation of the homologous recombination (HR) signaling pathway (middle). In the HR, the phosphorylation of the Ser-139 residue of the histone H2AX (γH2AX), is a master regulator of DNA damage response. Indeed, phosphorylation of H2AX by ATM and or ATR is placed in the DNA damage site for activation of downstream signaling pathways. NBS1 and MDC1 bind to H2AX to accumulate DNA damage repair proteins including MRE11, RAD50, and NBS1 (MRN complex), which in turn RNF8 ubiquitylates H2AX and H2A to recruit RAP80 and BRCA1 to DSBs for DNA repair function. On the other hand, accumulation of ATR, RPA (replication protein A), and TOPBP1 along with Rad17/RFC is critical for replication stress response in which the nick ends are coated by RPA filaments and replaced by RAD51 to locate the area of homology in the template DNA (right). Base excision repair (BER) addresses SSB, in which several DNA glycosylases can recognize damaged bases and orchestrated by XRCC1. To this end, PARP1 activates DNA lesions for POLβ-mediated DNA repairing and LIG1/3-mediated ligation in the short-patch (SP) BER. However, POLβ or POL δ/ε and a LIG1-mediated ligation are required for long-patch (LP) BER in response to oxidation stress. Double-strand ends also result from short telomeres. Therefore, any incorrect repair of DNA damage likely drives mutations in DNA damage repair proteins, thereby resulting in genomic instability as a hallmark of aging.

Telomere attrition

Telomeres are a protective cap on the ends of chromosomes that are shortened with each replicative cycle and cell division⁵¹. In addition to DNA damage, telomere shortening triggers a DNA damage response. When the shortening of the chromosomes reaches the “Hayflick limit,” it undergoes senescence or apoptosis⁵². It is well-documented that telomere length decreases with age^51,53 and evolves as a tumor-suppressive mechanism⁵⁴. To this end, excessive decreases in the size of telomeres are correlated with several aging hallmarks including metabolic syndrome, obesity, coronary heart disease, hypertension, osteoporosis, and cancer⁵⁵. Telomerase is an enzyme that efficiently increases the length of telomeres, whereas cancer cells, but not normal somatic cells, retain the abnormal function of telomerase for high replication⁵⁶. It is shown that long-lived species have short telomeres with a low level of telomerase⁵⁷, suggesting that short telomeres and telomerase suppression are essential for longevity. Moreover, mice with short telomeres are more susceptible to cancer⁵⁸. This suggests the controversial function of telomere shortening in the regulation of aging in animals. Senescent cells can secrete proinflammatory cytokines and or other factors in the extracellular matrix that potentiate the tissue microenvironment for tumorigenesis⁵⁹. However, whether senescence prevents old tissues from cancer needs more in-depth study. On the other hand, chemotherapy also accelerates aging demonstrated in hematologic and solid tumor malignancies⁶⁰. Chemotherapy likely triggers telomere shortening either directly or by inhibiting telomerase function. For example, cisplatin inhibits the activity of telomerase during the treatment of primary hepatocellular carcinoma⁶¹ (Fugues 1 and 2).

Genomic instability

Telomere shortening is correlated with genomic instability, which occurs in early tumor progression and represents a significant risk factor for aging-related diseases^12,14,43. Genomic instability is affected by many factors including chromosomal aneuploidies, copy number variations, somatic mutations, and DNA damage, which is increased by aging upon decline in DNA repair response⁶². DNA damage repair pathway is a critical cellular machinery in cell cycling for repairing DNA damage⁶³. As such, defects in timely repairing DNA trigger genomic instability to transform cells into malignancy. Genomic instability is also associated with neurologic disease, and osteoarthritis is another age-related outcome. On the other hand, cancer treatments using radiation therapy can also induce DNA damage for developing cancer⁶⁴. For example, chemotherapy using cisplatin can generate reactive oxygen species or free radicals⁶⁵ to damage DNA and increase the risk of secondary cancers⁶⁵. DNA damage can be measured by immunostaining for γH2AX, which accumulates at the damage site⁶⁶. However, the increased level of γH2AX is also associated with hypoxia-induced factor 1 alpha, HIF1α-driven tumorigenesis^67,68. Alkylating agents can also significantly facilitate the development of leukemia cancer^69,70. Lastly, Topoisomerase II inhibitors inhibit DNA repair enzymes and create genomic instability, followed by the developing second cancers, such as leukemia^71,72. Although advancements in technique and machinery have helped, the likelihood of developing post-irradiation secondary cancer is still much higher than after chemotherapy^73,74 (Figure 2).

Genome susceptibility

It is shown that mice with extra copy numbers of Trp53 (which encodes p53) and also cyclin-dependent kinase inhibitor 2A (Cdkn2a) display lower oxidative stress and strong cancer resistance⁷⁵. Moreover, mice with mutation and disruption in insulin-like growth factor I (IGF1) signaling have a smaller body size and less cancer incidence with extended longevity¹⁰. Interestingly, Laron syndrome patients with GHR deficiency have low serum levels of IGF1 and IGF2 and are also resistant to cancer⁷⁶. These results suggest that a reduction in cell proliferation can protect individuals from cancer and extend lifespan⁷⁷. Epidemiological studies support the idea that short and small people have a lower cancer incidence, which can be reflected by their lower level of cell proliferation⁷⁸. However, additional in-depth studies are warranted to validate this hypothesis.

Epigenetic alterations

Epigenetic changes have been hypothesized to play critical roles in both aging and cancer settings⁷⁹. Epigenetics can be considered as a type of modification in the chemical structure of DNA or DNA regulators, leading to a change in gene expression without affecting the DNA coding sequence⁸⁰. For example, DNA methylation occurs in the specific CpG dinucleotides during aging⁸¹. Notably, both global hypomethylation and promoter hypermethylation have been reported during cancer progression⁷⁹. Such modifications are also made to DNA regulators such as histone proteins, including methylation, acetylation, and ubiquitylation of histone proteins⁸⁰. Indeed, the average weight of epigenetic modification could be harnessed to predict chronologic age as an epigenetic clock⁸². These histone modifications along with DNA modification can influence the formation of cancer resulting from the regulation of the genomic instability that leads to chromosomal breaks, allelic loss, and translocations. Moreover, epigenetic alterations likely cause transcriptional activation and/or deactivation of proto-oncogenes and tumor suppressor genes to influence tumorigenesis. Such epigenetic age acceleration (EAA) indicates accelerated biological aging as an epigenetic clock that is associated with an elevated risk of several chronic diseases during aging^83,84. Individuals affected by EAA are epigenetically older than their chronologic age with the onset of age-related diseases including cardiovascular diseases, neurodegenerative dementia, and cancers^85–87. The evidence on EAA is rather limited in cancer survivors, but a higher level of EAA has been demonstrated in childhood cancer survivors⁸⁸.

Loss of protein homeostasis

Maintenance of correctly folding proteins and degradation of nonfunctional proteins are critical in cell survival⁸⁹. Therefore, loss of protein homeostasis or proteostasis can lead to an acceleration in cellular apoptosis. For example, macroautophagy is a responsible pathway for the degradation of defective organelles and aggregated or misfolded proteins for cellular homeostasis maintenance⁹⁰. The ubiquitin-proteasome pathway (UPS) is also another destruction system to eliminate dysfunctional and misfolded proteins through the 26S proteasome⁹¹. Therefore, aging is physiologically connected to a gradual inhibition of macroautophagy and or mitophagy^92,93. As such, dysfunction of macroautophagy reduces cancer metabolism, proliferation, resistance to therapeutic agents, and anticancer immune responses⁹⁴. Moreover, macroautophagy contributes to ferroptosis cell death as a tumor-suppressor and maintains genomic stability, oncogene-induced senescence, and diminishes inflammation⁹⁵ and supports immunosurveillance^94,96. Lastly, cancer therapeutics using ixazomib, a second-generation proteasome inhibitor, which is used in the treatment of multiple myeloma can accelerate aging⁹⁷. Thus, macroautophagy and the UPS may play a double role either by supporting or preventing tumor progression and providing altered homeostasis during aging⁹⁸.

Vascular aging and angiogenesis

Tumor angiogenesis is necessary for cancer cell growth in the solid tumor microenvironment, thereby vascular system provides angiogenic support for aging tissues. Notably, VEGF and angiogenesis processes are found to be reduced in aging mice, and antagonizing this process can promote healthy aging and extend life span⁸⁹. On the other hand, the aging of the vascular system prevents the development of solid tumors in old age⁹⁹. It has been reported that a reduction in the capacity of vascularization slows the growth of tumor cells in older mice compared with younger animals^100,101. The reduction in the growth of tumors was also detected in mice with genetically engineered atherosclerosis-prone apolipoprotein E-deficient (Apoe)^−/− mice¹⁰⁰, suggesting that vascular aging is critical in tumor regulation.

Deregulated nutrient sensing

It has been shown that calorie restriction significantly reduces cancer incidence and increases lifespan in numerous species but not all strains^102,103. Excess adipose tissue and obesity correlate with age-associated diseases and a shorter lifespan^104–106. Whether the effects of calorie restriction (CR) are associated with cancer progression is poorly understood and the underlying molecular mechanisms remain to be clarified. Potential molecular mechanisms of CR include the energy sensor AMP-activated protein kinase (AMPK) and sirtuins, for example, SIRT1, which has been assumed to be a key player in CR¹⁰⁶. High activity of the GH-IGF1 signaling pathway has also been associated with tumor progression¹⁰⁷. Moreover, the PI3K pathway, and several associated factors such as AKT, PTEN, and mTOR, have also been correlated with aging¹⁰⁸. The mammalian target of rapamycin (mTOR) is the center of the nutrient-sensing signaling pathway that regulates cellular metabolism¹⁰⁹. It is shown that inhibition of mTOR signaling using Everolimus in neuroendocrine tumors, breast cancer, and renal cell carcinoma is associated with aging phenotype in mice¹¹⁰, leading to impaired wound healing, insulin resistance, and testicular degeneration¹¹⁰. Therefore, the PI3K/AKT/mTOR pathway is a potential target in the regulation of the anticancer effects of CR and has also been correlated with aging (Figure 3).

Figure 3. Potential relationship between hypoxia, aging, and cancer cell signalings.

Hypoxia is a pathophysiological condition due to the imbalance between consumption and vascular support of O₂ to the cells. In normoxia, prolyl-4-hydroxylases (PHDs) hydroxylate HIF-α subunits (HIF1α and HIF2α) on proline residues to be bound with the von Hippel–Lindau protein (pVHL) for proteasomal degradation of HIF-α. Moreover, HIF-α is hydroxylated on asparagine by factor inhibiting HIF-1 (FIH) in the non-hypoxic conditions that prevent binding of HIF-α to the p300/CBP which are co-activators for HIF-mediated transcription. In the hypoxia condition, the activity of PHD and FIH is limited, leading to the accumulation and translocation of HIF-α subunits into the nucleus for dimerization with HIF1β, a constitutively expressed subunit. Transcriptional regulation is initiated when HIF-1 binds to the hypoxia-responsive elements (HREs) on the promoter of HIF-target genes. HIF-α promotes the expression of several genes involved in cell survival, metabolism, immune invasion, etc. On the other hand, the synthesis of HIF-α proteins is upregulated by mTOR signaling, while the mRNA level of HIF-α is regulated by STAT3 and NF-κB signaling. In addition, the Mnk kinases play critical roles in regulating mRNA translation. They are phosphorylated on Thr 197/202 by the p38 and Erk1/2 mitogen-activated protein kinases (MAPKs) for consequent interaction with eIF-4G which is essential for eIF-4E targets such as protein synthesis of HIF-α.

Endocrine changes with age

Endocrine changes may contribute to cancer susceptibility with aging and decrease cancer incidence. These include sex hormones such as estrogens and androgens, which typically decline with age¹¹¹. Notably, androgens, estrogens, and progesterone likely increase postmenopausal ER-positive breast cancer risk¹¹². Furthermore, the levels of GH and IGF1 are reduced by age^113,114, and low levels of GH and IGF1 have been associated with a reduction in cancer incidence. This suggests that the expression of endocrine regulates cancer development in old people. For example, anorexia is found as an eating disorder with abnormally low body weight, and or an intense gaining weight⁸⁹. Anorexic women reveal a lower incidence of breast cancer with a reduction in the levels of IGF1 and estrogens, suggesting that anorexia is similar to calorie restriction and may protect humans against cancer¹¹⁵. Intermittent fasting also decreases IGF1 levels and keeps normal cells from cytotoxicity of chemotherapy in mice¹¹⁶. Herein the efficacy of fasting before chemotherapy is under investigation in cancer therapy¹¹⁷.

Alterations in immune checkpoint

It is well-known that the immune system is compromised during aging and or undergoes immune-senescence¹¹⁸ followed by inflammation^119,120. Inflammation occurs during aging in response to higher levels of inflammatory cytokines, such as interleukin-6 (IL-6) and or tumor necrosis factor (TNF)^119,121,122. Inflammation can also drive the senescence of cancer-associated fibroblasts (CAF) that secretes factors for the dissemination of tumor cells¹²³. Furthermore, the capability of the immune system in the recognition and elimination of pathogens, termed immunosurveillance, is also compromised during age and contributes to the progression of cancer in old age¹²⁴. Aging of the immune system (immunosenescence) may directly affect T cells for down-regulation of the costimulatory molecules, CD28 and CD27, and upregulation of the terminal differentiation molecule, CD57, to reduce their effector function^125,126.

Immune checkpoint proteins are on the surface of immune cells regulating the immune system and sending an “off” signal to the T cells. These signaling pathways are critical for self-tolerance to prevent an immune response that destroys healthy cells in the body. However, some cancers can not only protect themselves from T cells, but also attack via stimulating immune checkpoint targets. For example, immunotherapy using PD-1 blockade antibody can stimulate immune checkpoints, leading to a proinflammatory phenotype associated with aging⁹⁷. Recently, several studies have attempted to activate immune responses against senescent cells by engineering chimeric antigen receptor (CAR) T cells, leading to the recognition of antigens related to cellular senescence^127,128. Moreover, senescent macrophages are accumulated in tissues to facilitate KRAS-induced cancers¹²⁹. Hence, the elimination of senescent macrophages can inhibit tumor progression^129,130. Therefore, aging tissues may have the potential for tumor initiation and invasion. However, it is not clear whether the higher incidence of cancer is due to a reduction in immune surveillance or a higher incidence of infection with pathogens in the elderly population¹³¹ (Figure 1).

Stem cell exhaustion

It is shown that stem cells are exhausted during aging¹³², leading to clonal hematopoiesis and hematogenous malignancies. The kinetics of hematopoietic cell transplantation (HCT) stimulate replicative stress and shorten telomerase in the stem cell lines for consequent stem cell exhaustion in recipients rather than those of donors¹³³. The stem cell exhaustion is likely due to shortening telomeres, followed by replicative stress during hematopoietic reconstitution¹³⁴. Replicative stress delays recovery of cell lines and distorts hematopoiesis after HCT, leading to a decline in physiologic aging¹³⁵ and increasing the chance of secondary cancer¹³⁶. Interestingly, using younger HCT donors could significantly increase the 5-year survival rate¹³⁷. Therefore, younger HCT donors are always preferable to their older siblings to increase cellular age in recipients¹³⁸.

Hypoxia signaling at the crossroads of aging and cancer

It has been shown that hypoxia increases tumor progression and metastasis, and is associated with poor survival in cancer patients¹³⁹. The hypoxia-inducible factors (HIF), which is a family of heterodimeric transcriptional regulators, control several genes related to glucose metabolism, erythropoiesis, and angiogenesis¹⁴⁰. Hence, understanding how senescence regulates both proliferative cancer and aging cells would be important in the hypoxia field. Cellular senescence has a critical event as a programmed tumor suppressor function to remove damaged cells from a population of normal cells with aging¹⁴¹. It is shown that the replication capability of cells is exhausted by cellular senescence with age⁸⁹. Tissue hypoxia is also increased with aging and inhibits senescence, but it can inhibit tumor suppressors and activate angiogenesis for the initiation of tumor progression.

Many studies show that cellular senescence can be prevented by lower levels of oxygen or hypoxia^142–144. The increased level of mitochondrial reactive oxygen species (ROS) triggers oxidative stress¹⁴⁵, leading to the induction of cellular senescence^146,147. Conversely, lower oxygen reduces ROS production and rescues senescence^143,144. Therefore, the correlation of ROS by the level of oxygen and also senescence remains to be further clarified^148–152. It is shown that reduction in the mitochondrial ROS by the hyperoxia is inadequate to prevent senescence in different tissues¹⁵³, suggesting that the function of ROS is in a cell and tissue-dependent manner. Although a low level of oxygen reduces senescence, the hypoxia/HIF1α signaling can also promote senescence in a cell-type-dependent manner in response to environmental stimuli (Figure 3).

Hypoxia-mediated cell cycle regulation

Cell cycle progression normally occurs when the oxygen supply is sufficient, termed normoxia^143,144. However, when the level of oxygen changes into the hypoxia condition it stimulates a G1/S arrest in a HIF1α dependent manner. Mechanistically, hypoxia/HIF1α signaling drives transcriptional regulation of CDKN1A (p21)¹⁵⁴ and CDKN1B (p27) genes that are involved in the cell cycle progression^155,156, but HIF1α also repressed CSC25A transcription¹⁵⁷. When the lack of oxygen or anoxia occurs, the cell cycle is arrested independent of HIF1α^158,159. On the other hand, silencing p21 is critical by the binding and or displacement of Myc on the promoter of p27¹⁵⁴, which might compete with HIF1α in the cell type and context-dependent manner in response to the level of oxygen. Moreover, HIF1α and HIF2α regulate the cell cycle and cellular proliferation in the opposite direction. For example, HIF2α promotes tumor growth at least in clear cell renal carcinoma,while HIF1α may inhibit proliferation^154,160.

Hypoxia-mediated cell metabolism

Hypoxia signaling promotes angiogenesis and lymphangiogenesis and adjusts the cellular metabolism for cell survival¹⁶⁰. When the oxygen level is decreased, the metabolism of the cells is also changed from aerobic to anaerobic metabolism. To this end, HIF1α transcriptionally regulates several genes (such as GLUT1, GLUT3, GAPDH, PGK, PGM, PGI, PK, etc.) for the activation of the glycolytic pathway¹⁶¹. The Warburg Effect is characterized by an increase in the level of glucose uptake and a shift from oxidative phosphorylation to rapid aerobic glycolysis to produce a high level of lactate in tumor cells^162,163. This adaptation occurs even under non-hypoxic conditions by the production of ATP in the mitochondria¹⁶¹. Glycolysis can also extend lifespan in part by reduction of oxidative stress. To this end, both phosphoglycerate mutase (PGM) and Phosphoglucose isomerase (PGI) are over-expressed for the reduction of cellular senescence, in contrast, depletion of these genes promotes premature senescence¹⁶⁴. Therefore, the hypoxia/HIF1α signaling can reduce cellular senescence through the activation of the glycolytic pathway for reduction of oxidative metabolism.

Hypoxia and telomerase activity

It is shown that a low level of oxygen can extend cellular lifespan¹⁴³, and the shortening of telomeres induces cellular senescence. This suggests a possible mechanism that might connect hypoxia to telomerase activity. HIF1α can target hTERT as a telomerase active subunit to be involved in cancer progression^165,166. Moreover, hypoxia can upregulate telomerase to significantly extend the longevity of human fibroblasts¹⁶⁷. Therefore, hypoxia inhibits cellular senescence, likely through multiple mechanisms.

Hypoxia-mediated activation of the p53 pathway

The p53 gene is a transcription factor and a central mediator of cellular senescence¹⁶⁸. p53 is also known as a tumor suppressor^169,170 and regulator of cell cycling¹⁷¹, and cell death programs¹⁷². Hypoxia is not only required to activate p53¹⁷³, but also the interaction of HIF1α with p53 has the potential to regulate cellular senescence¹⁷⁴. It is shown that the protein interaction of p53 with HIF1α promotes p53 stabilization and or HIF1α degradation^175–178. Moreover, p53 indirectly targets PML to induce cellular senescence^179,180. In contrast, hypoxia induces MIF, as a HIF1α target gene, to bind p53¹⁸¹ and reduce several p53-mediated responses^182–185, and senescence¹⁸⁶. Therefore, HIF1α and p53 regulate several mechanisms in opposite directions, likely in a cellular context-dependent manner (Figure 4).

Figure 4. The crosstalk between DNA damage, mTORC1, and apoptosis signaling pathways.

Various treatments induce replication stress even without DNA damage in which hypoxia is one of those leading ATM and ATR activation²⁵⁷. ATM phosphorylates MDM2 at Ser395 to induce its binding to the mRNA of p53²⁵⁸. ATR also phosphorylates MDM2 to bind and polyubiquitinate p53 for its proteasomal degradation²⁵⁹, and to lower the nuclear export of p53 mediated by MDM2²⁶⁰. Interestingly, HIF-1α transcriptionally regulates p53²⁶¹, and overexpression of MEK1, an upstream MAPK activator, also promotes the activation of both p300 and HIF-1α²⁶². In addition, p21^cip1/waf1 as a well-known CDK inhibitor binds with and inhibits cyclin-CDK2, leading to inhibition of cell cycle progression during G1 and S phases²⁶³. Cyclin D and cyclin E activate cdk4/6 and cdk2, respectively, leading to hyperphosphorylation and release of Rb protein and activating E2F-responsive genes. In addition, the CDK inhibitors such as p15, p16, and p21 inhibit cdk4/6, whereas p21 and p27 inhibit cdk2. On the other hand. the Ras-MAPK and PI3K-mTORC1 pathways regulate each other through cross-inhibition and or cross-activation. Moreover, Components of the Ras-ERK signaling pathway (Ras, Raf, ERK, and RSK) positively regulate the PI3K-mTORC1 signaling pathway in which TSC2 and mTORC1 are key integration proteins that negatively regulate each other²⁶⁴. Lastly, the Akt which can be localized to the nucleus phosphorylates CDK2, leading to cytoplasmic localization of the CDK2–cyclin-A complex²⁶⁵.

Hypoxia and oncogene-induced senescence

It is shown that oncogene-induced senescence (OIS) is critical in tumor suppression. For example, overexpression of HRAS induces senescence, which is associated with the increase of p53 and p16 in several cells¹⁸⁷. However, HRAS-induced senescence resulted from ROS production in low oxygen conditions¹⁴². Senescence is also regulated by various tumor suppressors such as pRb and p53 in the cells for the maintenance of cell-cycle arrest. Moreover, a benign tumor of melanocytes is frequently driven by a mutation in the BRAF gene¹⁸⁸ which is similar to HRAS and other oncogenes that drive cellular senescence in vitro and in mice^189,190. Furthermore, the loss of VHL induces senescence mediated by pRb in mouse fibroblasts¹⁹¹. Of note, VHL is a critical E3 ligase for driving ubiquitylation and proteasomal degradation of HIF1α or HIF2α in normoxia conditions¹⁹². Indeed, loss of VHL induces senescence through the regulation of p27 and p400 in a HIF-independent manner, which in turn activates pRB to function on cell cycle arrest and cellular senescence¹⁹¹. When the level of oxygen is reduced to be hypoxic, the loss of VHL is not sufficient to induce senescence in renal epithelia in vivo, which on the other hand, increases sensitivity to oxidizing agents for driving senescence.

Therefore, senescence may not be sufficient in vitro versus in vivo in response to lower oxygen levels. In addition, the Mnk kinases play essential functions in the regulation of mRNA translation thus they are key factors for cancer progression, drug resistance, and increasing proinflammatory cytokines¹⁹³. The Mnk kinases are phosphorylated on Thr 197/202 by the p38 and Erk1/2 mitogen-activated protein kinases (MAPKs) and interact with eIF4G for phosphorylation of their targets. Interestingly, overexpression of eIF4G prevents autophagy, apoptosis, and senescence upon ionizing radiation in breast cancer cells¹⁹⁴ (Figures 3 and 4). In addition, Mnk1 can phosphorylate and accumulate hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) in the cytoplasm of senescent cells, suggesting that Mnk kinases may regulate cellular senescence¹⁹³, but the underlying molecular mechanisms warrant in-depth studies.

Hypoxia-mediated senescence-associated-secretory-phenotype

The senescence-associated-secretory-phenotype (SASP) is associated with the secretion of several cytokines (such as IL-6, IL-7, and IL-8), and growth factors (such as HGF, GRO, and IGFBPs), for cell survival, inflammation and or immune-modulation¹⁹⁵. The SASP can stimulate both pro-malignant and premature senescence in the cells. For example, the chemokine receptor, CXCR2, and its ligands, GROα and IL-8, are critical factors for the induction of senescence¹⁹⁶. Moreover, an inflammatory cytokine such as IL-6 and IL-8 are required for oncogenic function of BRAF-induced senescence¹⁹⁷. To this end, plasminogen activator inhibitor (PAI1) downstream of p53 signaling regulates the induction of senescence¹⁹⁸. Interestingly, hypoxia can regulate HIF1α target genes including IL-8, PAI1, and CXCR-2 in several different cell types^199–203, and also upregulates IL-6 and or GROα expression in chronically hypoxic carotid bodies and hypoxic pulmonary arteries, respectively^204,205 (Figure 1). On the other hand, hypoxia restricts the SASP in part through AMPK-mediated suppression of mTOR signaling pathway²⁰⁶. Indeed, hypoxia activates AMPK-mediated suppression of the mTOR-NF-κB signaling loop, leading to less production of harmful pro-inflammatory SASP factors in both senescent cells and hypoxic tissue microenvironment²⁰⁶.

Therapeutic intervention

Several cancer therapies can contribute to the epigenetic age acceleration (EAAs) in cancer patients. For example, alkylating agents, doxorubicin, and radiation therapy can perform DNA hypermethylation and accelerated aging phenotype^79,207. Moreover, Topoisomerase II inhibitors, microtubule inhibitors, cross-linking agents, and methotrexate induce DNA hypermethylation, accelerating aging⁷⁹. Furthermore, epigenetic modifiers such as DNA methyltransferase inhibitors (5-aza-2′-deoxycytidine [5-aza]), histone deacetylase inhibitors (panobinostat, vorinostat), histone acetyltransferases (curcumin), and histone methyltransferases (BRD4770) induce senescence in preclinical models^208,209. For instance, 5-aza induces senescence in osteosarcoma, liver cancer, and lung mesothelioma cells, as shown by p16 INK4, senescence-associated β-galactosidase, and DNA damage response (DDR) signaling^210,211. Another drug, vorinostat, is FDA-approved for treating cutaneous T-cell lymphoma but induces senescence in leukemia, colon, and urothelial cancer cell lines^212–214. While drugs such as azacitidine and vorinostat are FDA-approved as anticancer drugs, their clinical evidence for regulation of senescence and aging is lacking.

Ongoing clinical trials evaluate the use of azacitidine in various malignancies²¹⁵, and only their completion will reveal its longitudinal effect on the human aging phenotype. Other small molecules such as rapamycin and resveratrol have effects on longevity and anticancer properties¹⁰². The use of rapamycin as an mTOR inhibitor in cancer treatment is also associated with increased longevity¹⁰², however, the effect of resveratrol in the extension of lifespan has been limited in obese animals^102,216. On the other hand, inhibition of mTOR by metformin activates AMPK through the tumor suppressor liver kinase B1 (LKB1) to inhibit cell growth^217,218. Notably, using metformin in patients with type 2 diabetes reduces the risk of cancer incidence²¹⁹ (Figure 1). Interestingly, the association of mTOR with SIRT1 is bidirectional and negatively turned²²⁰. SIRT1 (Sirtuin 1) is associated with diseases including aging^221,222 and periapical periodontitis²²³ (Figure 3). It is known that SIRT1 inhibits the expression of the NF-κß gene related to inflammation²²⁴, however, NF-κß more strongly inhibits SIRT1²²⁵. SIRT1 functions as a tumor suppressor to protect mice from breast and colon cancers^226,227. On the other hand, overexpression of SIRT1 has been also observed in some cancers such as leukemias²²⁸, suggesting that inhibition of SIRT1 may be promising for cancer therapies²²⁹. In addition, the SIRT1 enzyme and the poly ADP-ribose polymerase 1 (PARP1) enzyme both need NAD+ for activation. Of note, PARP1 is a DNA repair enzyme whose NAD+ levels are reduced by 20–30% in response to high DNA damage, followed by a reduction in SIRT1 activity²³⁰. These findings suggest that inhibition of PARP1 might reduce SIRT1 activation and lifespan. The use of PARP inhibitors has been established for the treatment of cancer patients.

Given that DNA damage contributes to aging through the regulation of apoptosis and senescence, and is also critical to maintaining genomic stability, thus the inhibition of DNA damage signaling requires a carefully targeted strategy (Figure 5). The use of other drugs such as aspirin, is associated with the extension of the lifespan in mice²³¹, however, the beneficial effects of aspirin are not well-known. To this end, The American Society of Clinical Oncology Guideline recommends a geriatric assessment (GA) for the early diagnosis and treatment of older cancer patients treated with chemotherapy²³². The GA considers functional and physical performance, medical conditions and cognition, nutritional and psychological status, and social support. Each one is an independent predictor rather than chronologic age in older cancer patients^232,233.

Figure 5. The common and opposing mechanisms driving the human aging-cancer cycle.

Cancer and aging are distinguished by common hallmarks such as genomic instability, epigenetic alterations, and chronic inflammation. There are also mechanisms of aging that typically block cancer cell growth and progression over time such as telomere attrition, cellular senescence, stem cell exhaustion, and macroautophagy inactivation. The common mechanisms are listed in the middle circle (orange color) and the noble mechanisms for aging (green color) and cancer (red color) are listed in the circles around the middle one. Negative regulation is shown as a blunt-ended line. NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; TLR: Toll-like receptor; TNF-α: Tumor necrosis factor; TP53: tumor protein P53; p21: cyclin-dependent kinase inhibitor 1; p16: cyclin-dependent kinase inhibitor 2 A; SASP: senescence-associated secretory phenotype; IL: interleukin; CCL2: chemokine C-C motif ligand 2; MYC: Myc signaling pathway; OCT4: octamer-binding transcription factor 4; KLF4: Kruppellike factor 4; SOX2: sex-determining region Y-box 2; WNT: Wnt signaling pathway; Notch: neurogenic locus notch homolog proteins signaling pathway; mTORC1: mammalian target of rapamycin complex 1; EP300: histone acetyltransferase p300; ATG: autophagy-related genes; MHC-I: major histocompatibility complex class I; IFN: interferon.

Senotherapeutics

Senotherapeutics has recently attracted interest in developing pharmacologic models to reduce senescent cells selectively. Senolytics inhibits senescence-associated antiapoptotic pathways (SCAPs) to alleviate phenotypes of senescent cells through the mitigation of SC effects which is called senomorphics²³³. Senolysis is a potential strategy to reverse age-related alterations using agents such as dasatinib and quercetin, which selectively induce apoptosis of the senescent cells of the bone marrow²³⁴. Moreover, the application of an anti-inflammatory agent such as fisetin, has been conducted in childhood cancer survivors to lower inflammation and insulin resistance²³⁴. Indeed, the combined administration of dasatinib and quercetin is an effective therapy leading to a direct cytotoxic effect²³⁵. The last agent is navitoclax which inhibits BCL-2 and promotes apoptosis of the senescent cells²³⁶. However, navitoclax can target a specific SCAP, whereas dasatinib, quercetin, and fisetin target senescent cells, suggesting that navitoclax has an unfavorable adverse effect.

Lifestyle

The relationship between nutrition, diet, and aging with cancer and or cancer therapy is not well understood. In the last decades, diet and nutrition have been involved in regulating telomerase activity, bioenergetics, DNA repair, and oxidative stress, leading to aging and cancer progression²³⁷. Lifestyle factors, such as obesity and smoking, can also influence cellular aging^238,239. In addition, dietary habits also affect cancer and aging through epigenetic alterations linked to the formation and progression of various neoplasms^240,241. It is found that cancer patients have increased psychosocial nervousness compared to non-cancer individuals²⁴². The elevated levels of psychosocial stress can activate the hypothalamic–pituitary–adrenal (HPA) axis, for increasing stress hormones, metabolic activity, reactive oxygen species, genomic instability, cellular damage, and inflammatory changes, leading to a decrease in telomerase activity, senescence, and accelerated aging²⁴³.

Furthermore, calorie restriction can not only prevent tumor progression, but also extend lifespan¹⁰⁶. For example, in a prostate cancer mouse model, calorie restriction decreases the level of plasma insulin, as well as IGF-1 signaling for the prevention of cancer²⁴⁴. Moreover, cancer survivors are likely affected by age along with direct (radiation, chemotherapy, targeted therapy) and indirect (frailty, weight gain) effects of cancer therapy^245,246. Cancer treatments affect hormonal levels as happens during androgen deprivation therapy in prostate cancer and or using aromatase inhibitors for estrogen antagonizing²⁴⁷. Cancer therapy can also increase IL-6 and C-reactive protein (CRP), leading to the induction of proinflammatory responses for accelerating aging²⁴⁸. Of note, IL-6 has been a well-known inflammatory biomarker associated with frailty²⁴⁹. Therefore, the management of diet including calorie restriction, along with aerobic exercise might reverse accelerated aging in cancer patients and cancer survivors. Although aging and cancer share a common mechanism for driving their phenotypes, cancer and its treatment may also negatively impact the human aging process (Figure 5). Therefore, therapeutic strategies for the treatment of cancer and aging might be carefully managed for effective therapy.

Discussion

Unraveling molecular aging is essential to develop effective therapies to fight aging in cancer survivors and prevent tissue aging and cancer development. It is a long way to understand why the rate of some tumors increases in early life in some individuals, why some tissue is more susceptible to cancer, and which genes are responsible for aging. Why do the response of the immune system and the level of the endocrine change with aging how do they interplay with cancer development? The interaction of aging and cancer is complex and their molecular landscape is varied in response to several physiological and pathological stimulators. The elevation of mutations with age is considered the main reason for driving cancer^250,251. However, the development of cancer is independent of aging in mice exposed to carcinogen-induced mutagenesis²⁵². This might be due to using different strains in response to diverse experimental conditions leading to controversy. The aging process initiates cancer growth in response to the increasing inflammation. However, the effects of aging on cancer might vary within different tumor and tissue microenvironments. It is shown that species with low serum levels of IGF1/2⁷⁶, smaller body size¹⁰, and short telomeres or less telomerase activity⁵⁷, are protective against cancer with extended longevity⁷⁷. However, stem cell exhaustion likely occurs due to shortening telomeres, followed by replicative stress during hematopoietic cell transplantation (HCT)¹³⁴. Thus, the effects of aging would also depend on the intensity of the aging immune system that fights against cancer or other pathogens (Figure 5).

Senescence is a defense mechanism to maintain tissue homeostasis and restrict tumor formation through the removal of damaged cells. However, the increasing number of senescent cells is a major reason for age-related inflammatory responses. Indeed, human cells undergo replicative senescence and a finite proliferative capacity, due to the shortening of the telomere which also triggers a DNA damage response. Such cellular senescence can also result in response to DNA damage by irradiation or chemotherapeutics, as well as losing the function of tumor suppressor genes, leading to mitochondrial dysfunction and elevation of reactive oxygen species which in turn, drive cellular DNA damage. The senescence-associated secretory phenotype (SASP) has also beneficial effects depending on the cellular context. For example, SASP can recruit immune cells to repair tissue by the removal of damaged cells and also promotes angiogenesis and tumor cell progression. However, the elevation of IL-6 and C-reactive protein (CRP) can induce proinflammatory responses for accelerating aging²⁴⁸.

It is well-known that hypoxia in normal tissue triggers tumor initiation and cellular senescence. This is in addition to what has been so far found hypoxia impacts tumor aggressiveness and cancer therapy. The activation of the hypoxia/HIF signaling pathway regulates several factors involved in senescence with conflicting signals. Induction of p21 by HIF signaling might be one of those incompatible signals that oppositely occur through the downregulation of p53 and thereby p21 in several cancer cell lines versus primary cells, respectively. In cancer-associated fibroblasts (CAFs), HIF-α regulates metabolic reprogramming and extracellular matrix (ECM) remodeling to support cell survival. Moreover, HIF-α activates the expression of cytokines that inhibit the adaptive immune system by activation of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory T cells (T_reg), leading to an immunosuppressive environment⁸⁹. Therefore, the sufficiency of hypoxia is required to induce cellular senescence in response to different physiological settings which is critical for the management of the senescence and survival balance. Therefore, adjusting mild hypoxia or oxygen gradients within tissues would be an important event to calibrate cellular senescence. Since stem cells are located in highly hypoxic areas²⁵³, this suggests why they are more resistant to oxidative stress. Hypoxic environments provide stem cells with a self-preservation mechanism from senescence^254,255 to maintain their self-renewal capacity. However, the Achilles heel of this mechanism is increasing susceptibility to oncogenic transformation. Therefore, the management of hypoxic tumor microenvironment would be beneficial to improve new therapeutic approaches.

It is well-known that the regulation of DNA repair mechanisms provides insights into designing better strategies to target cancer and mitigate risks for accelerated aging⁸⁹. The DDR is involved in cancer biology through novel cancer therapies by targeting DNA repair pathways. For example, poly-(ADP ribose) polymerase (PARP) inhibitors are synthetically lethal and have been established for the treatment of patients with BRCA1/2-deficiency. Moreover, platinum-based chemotherapies trigger DNA damage and eliminate cancer cells without DNA repair capacity. However, DNA damage participates in aging through the regulation of apoptosis and senescence, which can negatively affect the function of undamaged cells in the neighboring microenvironment by their SASP activation. Since DNA repair pathways are also critical to maintaining genomic stability, thus the inhibition of DNA damage signaling might promote cellular senescence and aging, which requires careful targeted therapy (Figure 5). In addition, aerobic exercise can maintain genomic stability by activating DNA repair¹⁶.

Future perspectives

The discovery of underlying mechanisms of cellular senescence and its function in human disease have great therapeutic potential for tissue remodeling, regeneration, and the treatment of aging and cancer. Aging tissues may have more potential for the development of cancers, however, the connection between aging and cancer may be lost over time in response to several stimuli in tissue microenvironment. These phenotypes are increased in aging and have a blockade function on cancer. Moreover, cancer and its treatment may negatively affect the human aging process. Chemotherapy and immunotherapy can induce cellular senescence in tumor cells and adjacent normal tissues, leading to telomere shortening, DNA damage, and apoptosis for accelerating aging and increasing the risk of secondary cancers. Therefore, the Inhibition of DNA damage and hypoxia signalings along with molecular components of aging and cancer might be carefully managed for effective therapy.