1 INTRODUCTION

The aging of the population with cancer has led to continued speculation about the link between cancer and aging. Aging is an unavoidable part of the human life cycle, characterized by a random accumulation of harmful events over time, leading to deterioration of the overall condition of the organism, increased risk of disease and death, morphological changes, functional deterioration, and metabolic dysregulation, resulting in reduced adaptability to the external environment. As individuals age, they often experience a variety of transformations such as genetic instability, the depletion of telomeres, epigenetic reprogramming, loss of proteostasis, a decrease in efficient macroautophagy, faulty nutrient detection, mitochondrial breakdown, the senescence of cells, a reduction in stem cell populations, changes in the communication between cells, persistent inflammation, and disturbances in their internal biological ecosystems.^{1, 2} Of these, features such as genomic instability, epigenetic reprogramming, and loss of proteostasis are already recognized as factors that can increase the risk of tumorigenesis, which seems to imply that there appears to be some link between aging and cancer.^3-6 Demographic findings clearly indicate that the prevalence and severity of numerous types of cancer rise as individuals grow older; around two-thirds of newly diagnosed tumors occur in individuals aged 65 years and over.^7-9 Exploring the correlation between aging and tumors is therefore crucial to unraveling the causes of tumors.

Cancer cells cause death through aging, leaving us with the subjective belief that aging inhibits cancer development.^{10, 11} However, recent findings indicate that the aging process can trigger the activation of a senescence-associated secretory phenotype (SASP) and deliver signaling molecules to cancer cells in the form of paracrine secretion to avoid apoptosis, stimulate cancer cell invasion and metastasis, as well as inhibit tumor immunity.¹² As research delves deeper, it has emerged that aging plays a bidirectional and complex role in tumor development, of which the relationship with tumor metabolic reprogramming is still unclear. Therefore, exploring the correlation between aging and the metabolic changes in tumors is crucial to uncovering the connection between aging and the onset of cancer.

Tumor cells can optimize energy supply through metabolic reprogramming, which promotes swift proliferation, invasion, and the metastasis of cancer cells, thereby accelerating the development of tumors. The main characteristics of tumor metabolic reprogramming are glycolysis, protein decomposition, lipid metabolism, mitochondrial biogenesis, pentose phosphate pathway, and other biosynthesis and bioenergy pathway upregulation. Current studies mainly focus on abnormal glucose metabolism, lipid metabolism, and amino acid metabolism. Carbohydrate is the most important energy supply substance in the cell, and the energy metabolism of tumor cells is mainly glucose metabolism. The main way of glucose metabolism in tumor cells is glycolysis. In other words, glycolytic within tumors is a critical component in the wider framework of cancer metabolic reprogramming. As early as 1924, German scientist WARBURG proposed the concept of “aerobic glycolysis” of tumor cells, that is, compared with differentiated cells, rapidly multiplying cancer cells will deplete a grand amount of glucose to carry out glycolysis and nonaerobic oxidation, even under the condition of sufficient oxygen and generate substantial quantities of lactic acid.^{13, 14} The rapidly multiplying cancer cells will expenditure a great amount of glucose for glycolysis instead of aerobic oxidation and produce a substantial quantity of lactic acid. The efficiency of aerobic glycolysis to produce adenosine triphosphate (ATP) is very low in normal cells, but tumor cells impair aerobic respiration in the presence of oxygen through a series of molecular mechanisms to carry out highly efficient glycolysis reaction, which results in a large amount of ATP,^15-17 as well as creating a microenvironment suitable for the survival of tumor cells, creating a proliferative advantage for tumor cells and enhancing their invasive and metastatic abilities.^{18, 19} The high flux of glycolysis not only provides energy rapidly but also supplies the essential elements for constructing a wide array of biological molecules in tumor cells.^{20, 21} For example, tumor cells are able to synthesize a mix of biomolecules by increasing glucose transporter proteins^22-24 or various key enzymes^25-27 to obtain a more efficient glycolytic reaction to promote metabolism. Second, lipids are a key component of cell membranes and other cellular organelles. Lipids maintain the fluidity of cell membranes and are important for the activation of molecules involved in plasma membrane signaling. Most tumor cells have the ability of de novo synthesis of fatty acids to continuously synthesize new membrane structures. In addition, the active proliferation of tumors requires a constant supply of amino acids for the synthesis of structural and functional proteins. The high metabolic demands of cancer cells and many biochemical reactions require large amounts of amino acids. Studies show that many cancer cells are amino acid dependent, which means that cancer cells lose the ability to synthesize certain nonessential amino acids and require additional supplies.

The occurrence of metabolic abnormalities is complementary to the change of signaling pathway. In addition, disruption of anabolic signaling reduces the organism's nutrition, and reduced nutrition-sensing signals seem to prolong lifespan and reduce cancer progression. However, common sense suggests that the body must be well nourished in order to have a strong immunity against cancer and prolong lifespan, and the two seem to be contradictory. Based on the above analysis, this paper intends to comprehensively analyze the relationship between aging and tumor metabolic reprogramming by summarizing the relationship between aging and tumor, as well as the similarities and differences between tumor and senescent cell metabolism, and explore the detailed relationship of its molecular mechanism. Meanwhile, this review analyses one of the key factors contributing to cellular senescence, namely, mitochondrial dysfunction, and analyses its relationship with tumorigenesis; since lipid metabolism occurs mainly in peroxisomes, we analyzed its effects on aging and tumor. Also, this review summarizes the current intervention strategies targeting the nutrient sensing pathway and the clinical cases of treating tumors for senescence features and tries to find the tumor treatment strategies based on targeting the senescence pathway. Finally, it also suggests rational dietary habits for people who want to fight aging. In conclusion, this review attempts to sort out the link between aging and metabolism and provide new ideas for cancer treatment.

2 THE LINK BETWEEN AGING AND TUMORS

It appears that the incidence and malignancy of many tumors increases with age. The latest data from Globocan 2022 can further visualize that there is an inevitable link between aging and cancer: from Figure 1A we can clearly see that the probability of developing tumors in humans increases significantly with age, with the incidence rates of cancer in the young, middle-aged, and elderly populations being 11.4, 35.6, and 53%, respectively; and at the same time, the mortality rate is also gradually climbing, with the number of deaths accounting for 57% of the incidence in the elderly ranking first in the pie diagram in Figure 1B. From the pie chart in Figure 1B, we can see that the number of cancer deaths among the elderly accounted for 57% of the number of incidence cases, ranking the first. This shows that the aging of the organism leads to a gradual decline in diverse body functions and a substantial rise in the occurrence of cancer, implying that aging can promote cancer.

To explore the link between aging and tumors, we need to understand the characteristics of each and whether there is a connection between these characteristics. Of the 12 features of aging, although three features such as loss of proteostasis, mitochondrial dysfunction, and altered intercellular communication^{28, 29} lack clear counterparts in cancer and the relationship between aging-associated nutrient sensing dysregulation and cancer-associated cellular metabolic reprogramming was unclear and required specific analysis for specific forms of metabolism, the remaining eight features, which form a direct correspondence with those of cancer (see Figure 2A), are: features common to both aging and cancer (genomic instability, epigenetic alterations, chronic inflammation, and environmental imbalance.); aging-antagonistic characteristic, that is, telomere shortening and stem cell weakening, that prohibit the emergence of certain features of cancer (capacity for infinite replication and phenotypic plasticity); and under specific circumstances, macroautophagy dysfunction inhibits the onset of cancer features (resistance to cell death), and the senescence program can deliver signaling molecules to cancer cells via SASP to avoid apoptosis.

Based on the relationship between senescence features and tumors, these eight features of senescence can be^{1, 25, 30, 31} divided into three categories: one category of features and those of cancer are mutually inhibitory, for example, telomere depletion induces permanent cell cycle arrest and destroys the feature of infinite replication of tumor cells; stem cell depletion leads to the loss of cellular plasticity required for tissue repair, and the continued differentiation of tumor cells hinders the sustained proliferation required for tumors.¹² The second category of features promotes tumors, such as genomic instability where DNA is damaged by endogenous and exogenous stimuli, and with aging this damage intensifies, resulting in altered activity of pertinent genes. This culminates in the development of cancer and epigenetic reprogramming causing extensive changes in the epigenome,^32-34 which favors changes in the ability to select features for phenotypic selection, can lead to clonal growth of tumor cells, enhancing proliferation and expansion; along with the aging process, the body usually experiences chronic inflammation, and immune cells promote tumor progression, by providing bioactive molecules to the tumor microenvironment.^35-37 Inflammation can promote a wide array of tumor signature functions; a good gut microbiota is important for maintaining human health, and aging of the body can easily lead to the destruction of the normal flora structure,³⁸ which causes ecological dysregulation leading to tumorigenesis. The third group of features refers to macroautophagy disorders and cellular senescence, which have a dual effect on tumorigenesis. It has been found that the articulation of genes related to autophagy ATG5, ATG7, and BECN1 decreases with age.³⁹ Knockdown of ATG5^{40, 41} and ATG7⁴² significantly accelerates cell-autonomous senescence, and a transient inhibition of autophagy can significantly promote tumorigenesis, suggesting that autophagy can play an oncostatic role by inhibiting the property of tumor cells to resist cell death; overexpression of ATG5 transgene⁴³ or BECN1^{44, 45} gain-of-function mutation can stimulate autophagy, delay senescence, and reduce the incidence of tumors.

In addition to the direct links, some features of senescence lack clear counterparts in cancer, but they may play an indirect role in inducing or inhibiting specific features of cancer, as shown in Figure 2B. Macroautophagy dysfunction may induce the onset of genomic instability and mutations in cancer features; loss of proteostasis may favor cancer features to resist cell death; mitochondrial dysfunction and cellular senescence may induce metabolic reprogramming of cancer trait cells; cellular senescence, altered intercellular communication, chronic inflammation, and ecological dysregulation may induce tumor cells to undergo immune escape. Cellular senescence may block the mechanism of infinite replication of tumor cells and inhibit cancer proliferation. What is more, the relationship between senescence-associated nutrient sensing dysregulation and cancer-associated cellular metabolic reprogramming remains unclear and needs to be analyzed specifically for specific metabolisms. Body metabolism includes glucose metabolism, lipid metabolism, protein/amino acid metabolism, nucleotide/nucleic acid metabolism, and other nutrient metabolism. Various substance metabolisms are interconnected and interact with each other, and metabolic signaling pathways interact to form a complex metabolic network. The metabolic pattern of tumor cells is very different from that of normal cells. Tumor cells reprogram their metabolic pattern, which contributes to their rapid growth. The main features of metabolic reprogramming in tumor cells include upregulation of glycolysis, amino acid metabolism, lipid metabolism, mitochondrial biogenesis, pentose phosphate pathway, and other biosynthetic and bioenergetic pathways. Among them, glycolysis, lipid metabolism, and amino acid metabolism are the main energy supply modes in tumor cells, which are also altered in senescent cells. In summary, in this section, we have discussed the relationship between aging and tumors, and we will next focus on a more in-depth discussion of the links between aging and glucose metabolism, lipid metabolism, and amino acid metabolism in tumors.

3 AGING PROMOTES METABOLIC REPROGRAMMING IN TUMOR CELLS

Tumor cell metabolic reprogramming is a key feature in tumor biology that involves significant changes in multiple metabolic pathways to accommodate the rapid proliferation of tumor cells. Glycolysis is one of the most prominent features of tumor cell metabolic reprogramming. While this modality is not as high as oxidative phosphorylation in terms of net ATP production, cancer cells compensate for this deficiency by promoting higher rates of glycolysis through increased glucose uptake. Second, lipid metabolism is also a key component of metabolic reprogramming in tumor cells. Tumor cells meet the biosynthetic demands of the cell membrane by enhancing lipid synthesis, which is important for rapid tumor cell proliferation and migration. Amino acid metabolism is also significantly altered in tumor cells. In particular, glutamine metabolism is upregulated in tumor cells to support the biosynthetic needs and energy production of tumor cells. Next, we will delve into the interconnections of glucose metabolism, lipid metabolism, and amino acid metabolism in aging and tumor processes. This part of the study will focus on revealing how these metabolic pathways act and influence cellular function in aging and tumor development. We will analyze in detail how these metabolic changes contribute to tumor cell progression and the effects of aging on the three metabolic patterns in tumor cells. Through this in-depth analysis, we can better understand the complex metabolic relationship between aging and tumors and provide potential targets for future therapeutic strategies.

3.1 Glycolytic reprogramming in tumors

We know from the previous section that the relationship between aging-associated nutrient sensing dysregulation and cancer-associated cellular metabolic reprogramming remains unclear and needs to be analyzed specifically for specific metabolisms. In this paper, we will focus on the reprogramming of glucose metabolism. Glucose is the most important energy-supplying substance in the organism, and its metabolic pathway is mainly divided into glycolysis pathway, pentose phosphate pathway, and oxidative phosphorylation. Normal cells in aerobic conditions, mainly through oxidative phosphorylation to produce ATP; in anaerobic conditions, mainly through glycolysis to produce ATP, while the swift multiplication of cancer cells necessitates an escalated energy requirement during the growth process, leading to the process of reprogramming the metabolism of tumor cells. In 1924, the concept of aerobic glycolysis in cancer cells was first introduced by German scientist, WARBURG.^{46, 47} Compared with differentiated cells, tumor cells undergoing rapid proliferation tend to use significant amounts of glucose for glycolytic instead of aerobic oxidation, subsequently generating substantial quantities of lactic acid even when there is ample oxygen available (Figure 3A). Cancer cells consume glucose to produce pyruvate either aerobically or anaerobically. 85% of pyruvate undergoes glycolytic to produce lactate; only a small amount of pyruvate undergoes oxidative phosphorylation aerobically to produce CO₂. Normal cells aerobically glycolyzes ATP very inefficiently, but in tumor cells, glycolysis is 20–30 times more efficient than in normal cells.⁴⁸ The acceleration of glycolysis has been observed to have a positive correlation with the rapid expansion of tumor cells,^{15, 49} indicating a marked association with the aggressive advancement of malignant tumors.^{18, 50} This intricate relationship underscores the fundamental role played by glycolytic pathways in fueling the heightened energy demands characteristic of proliferating cancerous cells. The promotion of glycolysis not only provides a metabolic advantage to cancer cells but also contributes significantly to the metastatic potential and invasiveness exhibited by malignant neoplasms.

Although glycolysis capacity is less efficient compared with mitochondrial oxidative phosphorylation, aerobic glycolysis offers numerous advantages to the proliferation of cancer cells: (1) aerobic glycolysis produces ATP extremely fast,^{20, 50} which can immediately supply energy to rapidly proliferating tumor cells; (2) tumor cells can obtain a large amount of intermediate metabolites through aerobic glycolysis,^{20, 51} which are used to synthesize fats, proteins and nucleic acids to meet their active anabolic demands; (3) the process of aerobic glycolysis within tumor cells generates a high volume of lactic acid. This in turn causes an increase in acidity within the tumor's microenvironment.^{52, 53} This acidic shift has been seen to promote angiogenesis within tumor cells, enhance their invasiveness, and facilitate metastasis and evasion from immune responses; (4) the aerobic glycolysis in tumor cells has the ability to facilitate the expression of the hypoxia-inducible factor-1 (HIF-1).^54-56 This occurs through the molecular process wherein mTOR, a target downstream of phosphatidylinositol 3-kinase (PI3K)/Akt in tumor cells, plays a role in the transcriptional regulation of HIF-1. Consequently, this leads to an elevated level of HIF-1 expression within the tumor cells,⁵⁷ which results in high levels of HIF-1 expression, which in turn increases the manifestation of glycolytic enzymes such as hexokinase 2 (HK-2), M2-type pyruvate kinase (PKM2), and lactate dehydrogenase A (LDHA), along with the regulatory enzyme pyruvate dehydrogenase kinase isozyme 1 (PDK1).^{58, 59} The signaling pathways involved are shown in Figure 3B and are summarized below:

• (1)

  PI3K–AKT–mTOR pathway⁶⁰: PI3K activates AKT, which activates HK2, phosphorylates PFK, and activates mTOR to stimulate glycolysis.

• (2)

  Hippo pathway^{61, 62}: Activation of the Hippo pathway phosphorylates YAP/TAZ and induces HK2 expression via FOXC2, promoting glycolysis.

• (3)

  Myc signaling pathway^{63, 64}: Myc induces the glycolytic enzymes HK2 and PFK, which catalyze the corresponding glycolytic steps and promote glycolysis.

• (4)

  LKB1/AMP-activated protein kinase (AMPK) signaling pathway⁶⁵: LKB1 upregulates the expression of AMPK, a key target of AMPK, acetyl coenzyme A carboxylase (ACC), which this process facilitates the transformation of acetyl coenzyme A into malonyl coenzyme A.^{66, 67} AMPK inhibits ACC activity and promotes the level of intracellular glycolysis occurring.

• (5)

  Ras signaling pathway^{68, 69}: Upon stimulation by growth factors, the oncogene Ras is triggered into action. It interacts with the MEK protein, leading to the activation of MEK.^{68, 70} Subsequently, MEK in turn triggers the downstream substrate, ERK. This cascade effect ultimately boosts the expression of c-Myc, thereby facilitating glycolysis.

• (6)

  p53 signaling pathway: p53⁷¹ is able to transcriptionally activate SCO2^{72, 73} and other mitochondrial electron transport chain proteins to promote intracellular mitochondrial activity.

These are the signaling pathways involved in tumor aerobic glycolysis that have been reported so far.

3.2 Aerobic glycolysis in senescent cells

Senescent cells are characterized by morphological and metabolic changes, chromatin remodeling, altered gene expression, as well as the emergence of a proinflammatory phenotype known as SASP and a number of senescence-related markers, summarized as follows: (1) β-Galactosidase Staining Kit,⁷⁴ the increase in its activity reflects the increase in lysosomal content of senescent cells,⁷⁵ and is the most commonly used senescence marker. (2) p53⁷⁶ is a key regulator of cell cycle regulation, and its activation can lead to cell cycle arrest, thus triggering cellular senescence; phosphorylated p53⁷⁷ is a commonly used marker of cellular senescence. activation of the DNA damage response can lead to the phosphorylation of p53, thus leading to cellular senescence. (3) p21 is a key regulator of cell cycle regulation,⁷⁵ and its upregulation is one of the important markers of cellular senescence. p21 can inhibit the activity of CDK,⁷⁸ leading to cell cycle arrest, thus triggering cellular senescence. (4) p16 can directly inhibit the activity of CDK4/6,⁷⁹ which leads to cell cycle arrest and triggers cells to enter senescence. (5) LaminB1 is a structural protein of the nuclear membrane,⁸⁰ and its decreased expression is an important hallmark of cellular senescence. Downregulation of LaminB1 leads to heterochromatin decondensation and the production of cytoplasmic chromatin fragments, which cause DNA damage.^{75, 81} The downregulation of LaminB1 mRNA in transcriptomic studies is a widespread hallmark of cellular senescence. The general downregulation of LaminB1 mRNA in transcriptomics studies is a widespread hallmark of cellular senescence. (6) SASP includes increased secretion of extracellular matrix metalloproteinases, chemokines, cytokines and growth factors, and so on.⁷⁵ SASP is an important feature of cellular senescence, and its regulatory mechanism involves endoplasmic reticulum stress,⁸² cellular membrane composition, and other dimensions, which is a complex biological process. (7) When the cell is stimulated, Rb is phosphorylated⁸³ and thus loses its inhibitory effect, causing the cell cycle to enter the G1/S checkpoint and ultimately leading the cell to enter the senescent state. (8) γ-H2A.X⁸⁴ is one of the commonly used markers of cellular senescence and is an indicator of the DNA damage response. (9) 53BP1⁸⁵ plays an important role in DNA repair by binding to p53 and enhancing its transcriptional activity. But whether 53BP1 stays or not depends on γ-H2A.X. (10) Ki67 is a tumor cell proliferation marker that is not detected when cells are in the G0 resting phase. Senescent cells, on the other hand, are marked by a permanent exit from the cell cycle and therefore senescent cells do not express Ki67.⁸⁶

In addition to these markers, glycolysis also occurs in senescent cells, and the specific pathways are shown in Figure 4.This metabolic shift is evidenced by an upregulation of glycolytic enzymes and glucose transporter proteins, particularly GLUTs, enabling these cells to favor the glycolytic pathway for energy production. The biochemical processes of the TCA cycle and oxidative phosphorylation activity are not just fundamental to cell physiology, their nuances are proving instrumental in understanding the unique mechanisms of cellular energy production and consumption. In recent explorations, it has been observed that the TCA cycle and oxidative phosphorylation—the principal engines of energy production in cells—both exhibit increased activity,^87-89 which is somewhat different from tumor cells. In tumor cells, aerobic glycolysis is preferred, and mitochondrial respiration is relatively weakened. The activation and enhanced function of HIF-1α in malignant tumor cells precipitate a notable escalation in the levels of numerous critical glycolytic enzymes, including but not limited to HK-2, PKM2, LDHA and the pivotal regulatory enzyme PDK1.^{58, 90} The heightened activity of these enzymes results in elevated intracellular aerobic glycolysis, higher lactate levels, and a decrease in mitochondrial oxidative phosphorylation. In aging cells, aside from using glycolysis for energy, there is a significant oxidation of lactate to produce pyruvate to enhance mitochondrial respiration, unlike in actively dividing cells, which primarily depend on glycolysis for rapid energy production. Senescent cells show a marked reliance on the mitochondria to generate ATP through the oxidative phosphorylation pathway,^91-93 which in turn generates a large amount of reactive oxygen species (ROS).

3.3 Senescence promotes aerobic glycolysis in tumor cells

Glycolytic signaling pathways in tumor and senescent cells were elaborated separately, and we found that there seems to be some connection between senescence, tumor, and glycolysis. Current research seems to tell us that glycolysis inhibits cellular senescence. For example, Korolchuk et al.⁹⁴ found that knocking out the mitochondria of human embryonic lung MRC5 fibroblasts stopped cellular senescence, which was due to the fact that the destruction of mitochondria led to an increase in glycolysis, resulting in the production of an abundance of lactic acid, which in turn causes cells to escape aging, which allowed the cells to escape from senescence. Flores et al.⁹⁵ found that hair follicle stem cells normally break down glucose into pyruvate, which in turn generates lactate via the glycolytic pathway. If lactate production is blocked, the activation of hair follicle stem cells can be significantly inhibited; on the other hand, in a mouse model, lactate production within hair follicle stem cells is a key factor in promoting hair growth. When the secretion of lactate within hair follicle stem cells is amplified, it leads to a substantial acceleration in hair growth in mice. This phenomenon underscores the pivotal role played by lactate in regulating the proliferation and differentiation of hair follicle stem cells. This amplification in hair growth was attributed to the increased energy supply and metabolic reprogramming that lactate facilitated within the hair follicle stem cells.^96-98 Li et al.⁹⁹ found that when expression levels of the glycolytic key enzyme PKM2 are elevated, it can significantly diminish the aging of vascular endothelial cells.^{100, 101} These results undoubtedly indicate that glycolysis is a key enzyme in the growth of hair. These results are undoubtedly not suggesting that glycolysis can inhibit cellular senescence (Figure 5). Nevertheless, the preponderance of research within this domain has predominantly favored nontumorigenic cells, with only a scant number of studies meticulously probing the intricate relationship between glycolysis and cellular senescence within the confines of cancer cells. The significant paucity in scientific research has created a substantial lacuna in our comprehension of the mechanisms through which cancer cells modulate the metabolic pathways that undergo fundamental alterations during the aging process. This discrepancy in investigation not only hampers our understanding of the intricacies of cancer metabolism but also obstructs the potential development of effective therapeutic strategies targeting metabolic dysregulation in aging-related cancers. The dearths of insights into the synergistic interplay between the glycolytic profile and the aging mechanisms of tumor cells remain a conspicuous void, awaiting comprehensive exploration to elucidate the full spectrum of implications for cancer progression and potential therapeutic interventions.

The marked increase in tumor incidence with age has focused our attention on the cancer-promoting effects of aging. From a metabolic perspective, we know that tumor cells can alter energy metabolic pathways through metabolic reprogramming to accommodate their abnormal growth and reproduction needs. Senescent cells have the ability to spontaneously change their metabolism by producing an abundance of protein factors, known as SASPs¹⁰², which can impact the functioning of surrounding cells within the organism's microenvironment.¹⁰³ This process can be likened to the way glucose affects the body. Glucose, serving as the primary energy source for aging cells, undergoes metabolic transformations as well, with changes in the intensity of glycolysis in senescent cells^{104, 105} and TCA cycling activity of senescent cells¹⁰⁶ are changed. In the metabolic study of senescent cells, researchers found that senescent cells were able to further utilize oxidative phosphorylation metabolites such as citric acid, α-ketoglutarate fumarate, and malic acid to enhance cellular mitochondrial respiration and generate large amounts of ROS, which ultimately induced other cellular senescence.^107-109 Concurrently, senescent cells exhibit an increase in metabolites closely associated with glycolysis, such as lactate¹⁰⁴ and pyruvate, which stimulate the glycolytic process¹⁰⁷—a phenomenon reminiscent of the aerobic glycolysis observed in cancer cells. In addition, some genes related to glycolysis and TCA cycle in senescent cells, such as glucose transporter protein 1 (GLUT1),^{110, 111} phosphoglycerate isomerase (PGI),¹¹² phosphoglycerate kinase 1 (PGK1),¹¹³ and citrate synthase (CS), were also significantly upregulated. In conclusion, aging cells exhibit a distinct high metabolic phenotype characterized by enhanced glycolysis. The alteration of energy metabolic pathways as observed in the TCA cycle and oxidative phosphorylation is evocative of the metabolic reprogramming that occurs in tumor cells. This metabolic adaptation enables tumor cells to meet their increased energy demands and sustain rapid proliferation, despite the less efficient ATP production associated with glycolysis. Furthermore, the reprogramming of metabolic pathways in tumor cells not only fuels their growth and proliferation but also contributes to the development of an immunosuppressive tumor microenvironment. The dysregulated metabolism of tumor cells not only serves as a hallmark of cancer but also presents potential therapeutic targets to disrupt the energetic advantage of malignant cells (Figure 5A). We therefore speculate that senescence may promote aerobic glycolysis in tumor cells. In the following, we will argue our point of view in the light of currently available studies.

Senescence in tumor cells generates ROS that induce oxidative stress in neighboring tumor-associated fibroblasts undergoing aerobic glycolysis.^{114, 115} Senescence leads to oxidative stress in tumor cells,¹¹⁶ and this oxidative stress environment contributes to the shift of tumor cells toward aerobic glycolysis,^{117, 118} which promotes tumor development; in addition, in the intricate landscape of cellular biology, senescent cells—the aging or deteriorated cells that have ceased to divide—displayed a notable rise in aerobic glycolysis and the production of lactate that is contingent upon the activity of PDK4.^{119, 120} In turn, the large amount of lactate formed generates ROS, which ultimately contributes to the senescence of the surrounding cells and even the tissue system, and promotes tumor proliferation. In summary, although the research on senescence and tumor aerobic glycolysis is not in-depth, based on the above studies, we believe that senescent cells can spontaneously change their metabolism, just like tumor cells, and that senescence promotes aerobic glycolysis in tumor cells, which in turn promotes tumor malignant progression.

4 MITOCHONDRIAL DYSFUNCTION AND TUMORIGENESIS

In recent years, as people continue to deepen the study of aging, researchers have found that mitochondrial dysfunction will cause cells to accelerate and consume a lot of energy. In the long run, this high metabolism of the cell will be faster than ordinary cell aging. This confirms what people have long suspected: mitochondrial function is closely related to aging. Mitochondria serve as pivotal actors in the theater of cellular processes, with their primary role being the powerhouse that supplies energy via oxidative phosphorylation and engages in the intricate dance of cellular metabolism. The primary metabolic processes taking place within mitochondria include the citric acid cycle, the breakdown of fatty acids through β-oxidation, and the generation of ATP via oxidative phosphorylation. Due to the property of tumor cells to preferentially undergo aerobic glycolysis rather than oxidative phosphorylation for energy, researchers have speculated whether mitochondrial dysfunction is the structural basis for aerobic glycolysis in cancer cells. A substantial and growing body of scientific literature has provided compelling evidence supporting the association between mitochondrial dysfunction and the intricate process of tumorigenesis. Mitochondrial dysfunction refers to an impairment in the regular functioning of the mitochondria, which are essential cell organelles responsible for generating ATP and maintaining cellular energy balance. Numerous studies have indicated that dysregulation of mitochondrial function can lead to assorted pathological consequences, including the promotion of tumorigenesis. This disruption contributes to a host of cellular issues, which manifest in the form of altered metabolism, increased production of ROS, and initiation of apoptosis. It is within this context of mitochondrial perturbation that the correlation with tumorigenesis becomes particularly pronounced.^146-148 Furthermore, mitochondrial dysfunction is widely acknowledged as a key feature of the aging process, and it stems from a multitude of contributing factors (Figure 5B): anomalies in the enzymes of the TCA cycle,¹⁴⁹ the onslaught of oxidative stress,¹⁵⁰ alterations in the mitochondrial DNA (mtDNA),¹⁵¹ impairments within the electron transport chain,¹⁵² and irregularities in gene expression. Below we will describe the causes of mitochondrial dysfunction and the impact of these causes on tumorigenesis.

5 CELLULAR SENESCENCE AND APOPTOSIS CAUSED BY MITOCHONDRIAL DYSFUNCTION

It is well known that as cells age, the ability of cell proliferation and differentiation, and physiological functions gradually decline, which will eventually lead to cell death. Depending on whether it is controllable or not, cell death can be divided into two major categories, that is, programmed death and necrosis. Among them, programmed cell death includes apoptosis, pyroptosis, autophagy, necroptosis, iron death, copper death, and other forms. The most studied type of cell death is apoptosis. Cellular senescence and apoptosis are two different biological processes. Cellular senescence is a degenerative process, mainly related to pathological conditions associated with aging, and is usually triggered by a stress response due to damaging stimuli or abnormal proliferation. Apoptosis, on the other hand, is an active and orderly cellular suicide process, usually caused by various stimuli inside and outside the cell, such as DNA damage, oxidative stress, and mitochondrial dysfunction. These stimuli will activate the apoptotic signaling pathway in the cell, which will eventually lead to autonomous cell death.²¹⁷

In the previous section, we summarized the senescence-related markers, in which the relationship between the SASP and apoptosis drew our attention. Most of the SASP secreted by senescent cells contain proapoptotic factors, such as interferons like IFN-α and IFN-β, proinflammatory cytokines like TNF-α, IL-1β, and IL-6, as well as chemokines such as GM-CSF, CCL2, CCL3, CCL4, and so on. These SASP components can be activated by activation of immune cells (e.g., NK cells, macrophages, etc.), inducing cell membrane. These SASP components can induce cell membrane damage by activating immune cells (e.g. NK cells, macrophages, etc.) and ultimately lead to apoptosis of defective senescent cells.^{218, 219} In addition, some components of SASP, such as exosomes and ROS, can directly damage the cell membrane and lead to apoptosis. In other senescent cells, SASP seems to contain growth VEGF-A and PDGF-AA and other regenerative factors,^{219, 220} which may reduce apoptosis, tissue damage, and fibrosis compared with proapoptotic, proinflammatory senescent cells. In conclusion, there is a complex interrelationship between SASP and apoptosis. SASP can induce apoptosis through activation of immune cells or direct damage to cell membranes, but may also inhibit apoptosis in some cases, thereby promoting the propagation of the senescent phenotype.

Current research on the relationship between senescence and apoptosis focuses on the apoptosis resistance characteristics of senescence. During cellular senescence, some antiapoptotic signaling pathways, so-called “senescent cell antiapoptotic pathways (SCAPs),” are activated. During senescence, cellular resistance to apoptosis increases, resulting in the survival of functionally defective aging cells. This “age-related apoptosis resistance” may accelerate the aging process.²²¹ Among these SCAPs, we first noticed the PI3K–AKT–mTOR signaling pathway, which is also found in the aerobic glycolytic signaling pathway in tumour cells and in the glycolytic signaling pathway in senescent cells. Studies have shown that activation of the mTOR pathway promotes the expression of the inflammatory factor IL-1A, thereby enhancing SASP.²²² This enhancement of SASP can improve the antiapoptotic ability of senescent cells.⁸² On the other hand, long-term activation of the mTOR pathway leads to the loss of mTORC2, which causes insulin resistance,²²³ which in turn decreases the antiapoptotic capacity of cells.⁸² Besides, changes in p53 activity also affect apoptosis and senescence. On the one hand, p53 induces the expression of proapoptotic Bcl-2 family proteins and inhibits the expression of antiapoptotic Bcl-2 and Bcl-xL genes in a transcription-dependent manner, thereby activating apoptosis^224-226; meanwhile, p53 can also interact directly with Bcl-2 family proteins in a nontranscription-dependent manner, regulating the permeability of the outer mitochondrial membrane,²²² which in turn reduces the antiapoptotic capacity of cells.²²³ At the same time, p53 can also interact directly with Bcl-2 family proteins in a nontranscription-dependent manner to regulate the permeability of the outer mitochondrial membrane, promote the release of apoptotic factors, such as cytochrome c, and induce cell apoptosis.²²¹ Apoptosis induced by activation of p53 can accelerate the aging process. On the other hand, with the increase of age, p53 activity decreases, and p53-dependent apoptotic response will be weakened, leading to an increase in cellular resistance to injury, thus promoting aging. p53 activity decreases will also lead to alterations in cellular metabolism, increase glycolytic,²²⁷ and NF-κB²²⁸ pathway activity, which will enhance the cellular resistance to apoptosis and slow down aging.

So, senescence and apoptosis present a complex relationship. SASPs can induce or reduce apoptosis. Apoptosis plays an important role in organismal development and maintenance of cellular homeostasis, while changes in cellular resistance to apoptosis are an important mechanism leading to senescence.

6 THERAPEUTIC MEASURES THAT HAVE ENTERED THE CLINICAL PHASE

Presently, the primary approaches to treating tumors encompass surgical intervention, comprehensive chemotherapy, radiation therapy, therapy targeting specific molecules, and immunotherapy. In contrast to conventional chemotherapy treatments, targeted therapies offer a more accurate approach, minimizing harm to healthy cells while enhancing the efficacy of the treatment. ClinicalTrials.gov, an extensive database that has risen to global preeminence amongst clinical trial registries, was a collaborative venture created through the concerted efforts of the US National Library of Medicine and the US Food and Drug Administration. Conceived in 1997, this groundbreaking resource was officially unveiled in February 2002. Since its inception, it has been disproportionately influential in shaping the landscape of clinical research, and is, to date, the most prolifically utilized registry of its kind. In this database, we have comprehensively distilled the cancer-related clinical trials that included participants aged 65 years and above. Our aim was to pinpoint studies that simultaneously addressed the issues of “aging” and “tumor.” There are only eight signaling pathways targeted by such studies, namely, the PI3K/mTOR, JAK–STAT, GH/IGF-1, NF-κB, Hippo, Wnt/β-catenin, Notch, and AMPK signaling pathways; detailed data on completed and ongoing clinical trials are summarized in Table 1.

From the table, we can see that there are more clinical trials on aging and tumor-related signaling pathways, and the types of tumors treated are very rich, the drugs used are mainly everolimus, sirolimus, anastrozole, and so on, and there are more experimental protocols of combination drugs in recent years, which suggests that the combination of drugs is the focus area of tumor therapy and antiaging research in the future.

7 NANOTARGETING STRATEGIES WITH THERAPEUTIC POTENTIAL

In conclusion, in terms of clinical-stage therapeutic measures and developed nanotargeting strategies, existing studies have focused on the investigation of the PI3K/mTOR, AMPK, and Notch signaling pathway. It is hoped that more abundant research results will be available in the future to provide a theoretical basis for clinical treatment.

8 DIETARY ADVICE

Diet is an important part of human life, which, in addition to maintaining the normal vital signs of human beings, also reflects people's culture, health, and attitude toward life. As the social economy continues to progress and national living standards improve, there has been a discernible increase in the demand for food among the populace. Concomitantly, there is a heightened focus on the cultivation of dietary habits conducive to achieving and maintaining a state of optimal health. The burgeoning interest in healthy dietary practices can be attributed to a growing awareness of the profound impact that food consumption has on overall well-being. This trend is underscored by a plethora of studies illuminating the intricate relationship between dietary choices and health outcomes, thereby driving individuals to be more vigilant and discerning in their culinary decisions. In this section, we will make some dietary suggestions for antiaging and antitumor.

9 SUMMARY AND OUTLOOK

By analyzing the number of cancer incidence and deaths in different age groups, we determined that aging can promote tumorigenesis. Based on this conclusion we wanted to explore the relationship at the level of molecular mechanisms. It is clear that the relationship between aging and tumors is intricate. On the one hand, an environment of intracellular ecological dysregulation and inflammation results in genomic instability, epigenetic changes, loss of protein homeostasis, mitochondrial dysfunction, and altered intercellular communication in senescent cells. These factors contribute to the proliferation and malignant advancement of cancer cells. On the flip side, tumor cells need to overcome the antagonistic hallmarks of senescence, telomere shortening, and stem cell depletion, in order to maintain the infinite proliferation and phenotypic plasticity of tumor cells.

Regarding the metabolic relationship between senescence and tumors, some researchers have suggested that senescence-associated nutrient sensing dysregulation may lay the foundation for metabolic reprogramming in tumors. However, in fact, there is a contradiction between senescent cell metabolism and tumor cell metabolism, which needs to be analyzed in terms of specific metabolic modalities. Current findings suggest that glycolysis inhibits senescence in nontumor cells, but in tumor cells we have a different view. We know that tumors optimize energy supply through metabolic reprogramming, and that senescent cells, which use glucose as their primary energy source, similarly undergo metabolic changes. This led us to focus on exploring sugar metabolism in senescence and tumors. In tumor cells, senescence can generate ROS, leading to oxidative stress in tumor cells, and this oxidative stress environment helps tumor cells shift to aerobic glycolysis, thus promoting tumor development; in addition, senescent cells exhibit PDK4-dependent aerobic glycolysis, which promotes an increase in intracellular lactic acid production, and a large amount of lactic acid formed generates ROS, which ultimately contributes to senescence of peripheral cells and even the tissue system and promote tumor proliferation. Similarly, it has been shown that senescence promotes tumor cell growth and proliferation through lipid metabolism, and lipid metabolism in the tumor microenvironment similarly affects cellular senescence and thus immune resistance to tumors; moreover, knockdown of HNF4α or SAA enzymes impairs hepatic SAA metabolism, promotes epithelial–mesenchymal transition, and promotes malignant tumor progression. Structural and functional changes in immune system components in senescent cells, amino acid metabolism, and other pathways regulate adaptive and innate immune cells with altered hair differentiation and response, increasing susceptibility to disease and thus promoting tumorigenesis. In summary, we conclude that senescent cells can spontaneously alter their metabolism like tumor cells, and that senescence promotes aerobic glycolysis, abnormal lipid metabolism, and amino acid metabolism in tumor cells, which in turn promotes the progression of malignant tumors.

We also summarized the signaling pathways involved in tumor aerobic glycolysis as well as in glycolysis in senescent cells and found that some signaling pathways in tumor cells also play a role in cellular senescence, such as the PI3K–AKT–mTOR pathway and the Ras signaling pathway, and can promote glycolysis in tumor cells, leading to increased tumor cell proliferation. In tumor cells, activation of the PI3K–AKT–mTOR pathway⁶⁰ and the Ras signaling pathway can stimulate glycolysis, thereby enhancing the proliferation of tumor cells. We focused on the PI3K–AKT–mTOR signaling pathway because it plays a key role in cellular metabolic regulation and energy production. Activation of PI3K leads to cellular metabolic dysfunction and mitochondrial dysfunction that causes cellular senescence and promotes tumor progression. The upregulation of the YAP/TAZ activity in the Hippo pathway stimulates the transcriptional activation of HK2, which is pivotal in driving the glycolytic flux within cells promoting glycolysis. But YAP/TAZ activity is significantly downregulated in senescent cells, so the relationship between YAP/TAZ–HK2 regulation in senescent cells remains to be investigated. It is worth noting that cellular senescence leads to the generation of large amounts of ROS in the mitochondria, and the DNA damage caused by ROS can activate the classical oncogenic pathway P53 through p38/MAPK to play the role of oncogenicity; on the one hand, one of the markers of senescence SASP promotes the process of cellular senescence and inhibits tumorigenesis; on the other hand, SASP can also stimulate inflammation-related responses and promote tumorigenesis and development. On the other hand, SASP can stimulate inflammation-related responses and promote tumor development. This also proves the bidirectional role of senescence in tumor progression. Similarly, we have summarized the signaling pathways associated with abnormal lipid metabolism in tumor cells, such as NF-κB, STAT3, Hippo, Wnt/β-catenin, and Notch signaling pathways, which can all alter different aspects of lipid metabolism in tumor cells and increase lipid synthesis in tumor cells, thereby promoting tumor progression. It is noteworthy that senescent CAF have been found to enhance the formation of peritumoral tumors in GC through the JAK/STAT3 signaling pathway in the tumor microenvironment, which confirms our suspicion that senescence promotes the reprogramming of lipid metabolism during tumorigenesis and progression. In amino acid metabolism in tumors, we focus on amino acid classification and the specific biological roles of different amino acids in tumor cells. We found that glutamine is second only to glucose in importance in cancer, providing nitrogen and carbon to cancer cells and participating in a range of pathways including energy production, macromolecular synthesis, and signaling. Glutamate is converted to glutamine in large amounts during aging, causing metabolic disorders. It should be emphasized that both PI3K–mTOR pathway and AMPK pathway play a role in both tumor cells and senescent cells, and AMPK is activated in senescent cells, which participates in the regulation of cellular metabolism, affects intracellular amino acid levels, and alters the energy homeostasis of tumor cells, which in turn promotes their survival.

Since mitochondria are crucial in metabolism and one of the characteristics of senescence is mitochondrial dysfunction, we speculate that mitochondrial dysfunction is an important structural basis for cellular senescence and hence tumorigenesis. This is mainly achieved through mechanisms that induce oxidative stress, accumulation of mtDNA mutations, and effects on cell proliferation and growth. Factors contributing to mitochondrial dysfunction include defects in TCA cycle enzymes, mtDNA mutations,¹⁸⁰ electron transport chain, oxidative stress, and aberrant expression of oncogenes and oncogenes. In particular, mutations in mtDNA in cancerous cells result in a rise in free radicals and higher levels of ROS within the tumor cells, which stimulate the proliferative and invasive properties of tumor cells. Mutant KRAS overexpression causes oxidative stress in mitochondria and oncogenic KRAS-expressing cells show increased glycolytic activity, which promotes malignant tumor progression. In addition, the oncogene c-Myc also induced mitochondrial oxidative stress and upregulated the NF-κB signaling pathway, promoting tumorigenesis. The same lipid metabolism and amino acid metabolism occur on mitochondria, and abnormal amino acid metabolism is caused by mitochondrial translational malfunction and impaired TCA cycling in senescent cells. Amino acids require specific transporters to facilitate their role on mitochondria, but senescent cells cause mutations in their transporter SLC1A5, promoting tumor metabolic reprogramming. The lipid metabolism-related protein TRPC3 remodels Ca²⁺ release leading to mitochondrial dysfunction and promotes tumorigenic effects in senescent cells. In addition, peroxisomes, the main site of lipid metabolism, play an important role in cellular lipid metabolism and the degradation of ROS, but their dysfunction also promotes tumorigenesis due to the decline of peroxisomal activity with increasing age. We thus conclude that mitochondrial dysfunction in senescent cells leads to increased intracellular ROS or promotes glycolysis, lipid metabolism, and amino acid metabolism, which in turn leads to tumor formation. We also summarize the drug therapeutic trials and related nanomaterials that can be retrieved to target aging and tumor-related signaling pathways, with the research focusing on the PI3K/mTOR, AMPK, and Notch signaling pathway. In conclusion, we suggest that in our daily life, we need to optimize the composition and intake of our diet, and supplement some plant-derived nutrients appropriately to achieve the goal of improving their health and realizing healthy aging.

The mechanisms of tumor and aging as well as tumor metabolism and aging metabolism still need to be studied and explored in depth, focusing on the aging phenotypes in tumor cells and further delving into the intricate molecular mechanisms underlying the aging process is crucial in elucidating its multifaceted role in driving tumor progression. With the progress of science, we believe that one day in the future we can lift the fog shrouding aging and tumor and overcome the difficult problem of healthy aging.

AUTHOR CONTRIBUTIONS

Conceptualization, investigation, data curation, writing—original draft, writing—review, and editing: Yuzhu Zhang. Data curation, software: Jiaxi Tang and Can Jiang. Review: Hanxi Yi and Guang Shu. Corresponding, supervision, project administration, funding acquisition, review, and editing: Gang Yin. Corresponding, project administration, funding acquisition, review, and editing: Maonan Wang. All authors have read and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

Not applicable.