JAHP_13_4_1095-1115

Introduction

From the first moments of fertilization throughout the adulthood, series of physical and cellular keep changing, this process called aging, this process ends up with senescence and death. Numerous unique factors impact the aging rate during this process, generating changes in musculoskeletal, adipose, and cerebral tissue as physical and functional phenotypical alteration that are characteristic of older patients. These changes also impact the immune system (Franceschi et al., 2020). Skeletal muscle alterations are one of the most obvious effects of aging, which is a natural stage of life for all animal species. This is attributed to a variety of elements affecting the neuromuscular junction, canine muscle anatomy, and metabolism. The gradual atrophy and loss of individual muscle fibers, as well as the loss of both kinds of motor units, are the causes of the loss of muscle mass and strength. The pathophysiology of these alterations is connected to specific biological processes, such as oxidative stress, which damages and alters DNA sequences, mitochondria, and cell macromolecules. Additionally, one tissue that is particularly susceptible to this process is skeletal muscle (Pagano et al., 2015). Cellular senescence, stem cell exhaustion, mitochondrial dysfunction, loss of proteostasis, telomere attrition, epigenetic modification, genomic instability, altered intercellular communication, and deregulation of nutrient sensing are nine features of aging, particularly in mammals (Lopez-Otin et al., 2013). The prevalence of many aging-related disorders, such as neurodegenerative diseases, metabolic diseases, cardiovascular diseases, and others, is rising along with the world population’s age, making aging itself the most important risk factor for these conditions. These conditions lead individuals to become weakened, lose their ability to function normally, or even die (Knopman et al., 2021). Many factors, including telomere attrition, DNA shortening, epigenetic dysregulation, and chronic inflammation, contribute to the decline in stem cell’s ability to proliferate and regenerate as we age. Senescent cell accumulation and stem cell depletion result from decline in stem cell (Tenchov et al., 2022; Guo et al., 2022). Apoptosis, early differentiation, accumulating mutations, and cytostatic DNA damage checkpoint signaling are some of the processes that lead to stem cell exhaustion during ageing, which is also associated with DNA damage (Schumacher et al., 2021). One of the primary causes of aging is telomere dysfunction, which is the shortening of telomeric DNA with an increase in cell divisions. When this shortening reaches the Hayflick limit, telomere dysfunction triggers a reaction that damages DNA. The organism ages as a result of cell cycle arrest and proinflammatory factor production. Enhancements in telomerase activity and chromosomal integrity increase an organism lifespan. Telomerase activity regulates the length of telomeres (Zhu et al., 2019). Genomic instability is the term used to describe changes in DAN, such as variations in nucleic acid and sequence. These occurrences can have adverse impacts on gene expression, cell division, senescence, and death, which can change the genome nature (Saxena and Zou, 2022). A network of intracellular and extracellular interactions called protein homeostasis makes sure that newly produced proteins are translated and folded correctly and that misfolded proteins are refolded and degraded. As people age, these processes are diminished, which leads to a buildup of damaged proteins and organelles (Frankowska et al., 2022). Numerous cell-to-cell communication pathways, such as endocrine, neuronal, and neuroendocrine pathways, as well as cell-to-cell contact and the transfer of free-soluble and vesicle-packaged substances like inflammatory signals are all included in intercellular signaling, which is a feature of aging (Lopez-Otin et al., 2023). Gradual, decline in physiological functioning is a significant feature of normal aging in long-lived animals. The formation of reactive oxygen species (ROS) has increased in conjunction with this decline (Youngman et al., 1992) and an accumulation of macromolecules affected by nonenzymatic post-translational modifications that alter the structure and functionality of cellular proteins and tissue (Al-Okialy and Alwan, 2018). The main targets of ROS are proteins, lipids, and carbohydrates under oxidative stress. The carbonyl compounds produced by the oxidation of lipids and carbohydrates have the potential to directly or indirectly harm these big molecules (Miyata et al., 1998). Glycoxidation products like Ne-carboxymethyl lysine are produced when these carbonyl compounds interact with the amino groups in proteins (Motomiya et al., 1998). Aging, diabetes, and other diseases are characterized by tissue changes and cell dysfunction brought on by this glycoxidation process, which alters cell proteins (Al-Okaily and Murad, 2021; Khudair and Al-Okaily, 2022).

Aging in animals

Age is considered a factor for the study of animal populations, as many critical biological associates change over time. Biological functioning in terms of developmental stage, reproductive potential, disease burden, and mortality risk is frequently linked to age groups. These characteristics usually vary among distinct age groups, and the proportion of a population that falls into each age group helps conservation biologists predict the population’s future fitness (Perez-Pereira et al., 2022). The average lifespan of humans and animals has increased significantly due to modern advancements in technology, healthcare, and nutrition. While most dog owners are aware of the physiological changes that come with aging, such as changes in body composition, metabolic processes, and sensory abilities, many are unaware of the behavioral and cognitive changes that come with growing older and may or may not cause severe cognitive dysfunction (Larsen and Farcas, 2014). In addition to behavioral and cognitive changes, older dogs are known to exhibit a number of phenotypic changes. These include coat integument changes, impaired vital organic functions (hepatic, cardiac, lung, and renal), and an increased risk of many diseases, including musculoskeletal disorders, dental and ophthalmic diseases, and neoplasms (Creevy et al., 2016). For several specific diseases in dogs, including the majority of the main causes of canine death, aging is a significant risk factor. These diseases include degenerative neurologic or musculoskeletal disorders, cardiovascular disease, and neoplasia. Dogs’ lifespans and health are severely limited by the aging process, which can lead to common diseases and death (Lewis et al., 2018). Senior dogs currently make up 40–50% of canine patients at veterinary clinics, and as their percentages and average ages continue to rise, there is an increased emphasis on their health and well-being. The biological age of a dog, however, correlates with its chronological age but is different from it (Dhaliwal et al., 2023). In addition to the typical changes in coat texture, aging dogs often experience graying and thinning of their hair. Although conditions like allergic dermatitis, sun exposure, and other reasons can also cause these changes, older dogs also frequently have increased pigmentation, wrinkles, and a lack of skin suppleness. Reports of footpad calluses and hyperkeratosis are common (Angulu et al., 2018). Because calculus and tooth wear tend to develop over time, dental disease is commonly used as a predictor of age. In senior dogs, both benign and malignant neoplasms are common, and cutaneous and subcutaneous tumor formation is often associated with age (Stella et al., 2018). The proportion of fat mass in older dogs has increased relative to younger dogs, while older dog may have lost weigh overall. Degenerative changes in joints and a reduction in the suppleness of connective tissues are more musculoskeletal alterations. These changes add to the decline in activity and comfort, which is a frequent and serious worry for owners (Hutchinson et al., 2012). Cats skin and coat change as they age. These changes include hyperkeratosis and epidermal, dermal, and follicular atrophy, which can cause a thinning coat and focal alopecia, loss of melanocytes in the hair follicles, decreased skin elasticity, and decreased tyrosinase activity, which causes white hairs. Thus, this alteration can effectively impact on their overall comfort and well-being and appear as older cats. Additionally, healthy senior cats have been shown to have brittle claws (Vogt et al., 2010).

Older canines, in addition to the typical anatomical and functional alterations that the hearts, lungs, and kidneys undergo due to aging, exercise causes the hearts and lungs to lose their flexibility and functional ability. On the other hand, glomerulosclerosis, interstitial inflammation and fibrosis, and a decrease in glomerular filtration rate are common age-related alterations observed in the kidneys of aged dogs (Cianciolo et al., 2016). In addition to the behavioral and physical changes that accompany aging, dogs may also become less gregarious with people and other animals. Age has been linked to sociability in both healthy, cognitively normal dogs and dogs with age-related cognitive dysfunction (Bellows et al., 2015). As dogs age, they may exhibit increased fear responses and aggressive behavior (Riemer et al., 2021). Cats frequently show behavioral and physical changes as they age, including changes in attitude, activity, hunger, sleeping habits, and cognitive abilities. These changes frequently come from underlying neurological abnormalities (Gunn-Moore, 2011).

Theories of aging

Numerous theories are attempting to explain the complex process of aging, some of the most prominent ones:

Free radicals’ theory

Because defective (leaky) mitochondrial respiration is the primary source of endogenous ROS, the free radical hypothesis of aging suggests that aging comes from an accumulation of unstable molecules created by improper cellular metabolism. There is substantial evidence linking age-related illnesses to ROS and mitochondrial dysfunction (Lagouge and Larson, 2013). Highly reactive substances called reactive oxygen species (ROS) are produced in the mitochondria of cells and can have a beneficial or negative effect on a wide range of physiological processes. The body cells produce extraordinarily little ROS under normal physiological conditions, which is an indication of minimal oxidative stress. These molecules are essential for immune system support, cell to cell communications, and the regulation of cellular signaling pathways. However, when the level of oxidative challenge exceeds the normal physiological range, it can cause disruption and oxidative damage to large molecules (Al-Okaily, 2024). These extremely reactive oxygen-derived molecules, which are produced during aerobic metabolism, may in fact interact with biological components and cause cumulative oxidative damage over time, which could potentially shorten their lifespans (Harman, 2000). Elevation of ROS drives all cellular chemical components to be altered, including nucleic acids; all these changes will lead to cellular apoptosis by mitochondrial pathways (Bokov et al., 2004). Mitochondrial oxidative damage and a decrease in mitochondrial copy number have been linked to increased ROS production (Giorgi et al., 2018). These alterations are linked to a higher rate of mtDNA mutation in older people’s brains, livers, and muscle fibers (Fayet et al., 2002; Cahill et al., 2005). The development of common aging symptoms in humans, such as hair loss, weight and fat loss, decreased bone density, and cardiomyopathy, was related to a decrease in mitochondrial respiratory chain activity and an increase in mtDNA mutations (Trifunovic et al., 2005). The two mitochondrial respiratory chain complexes that have been investigated most are Complex I and Complex III. The molecular involvement of the ubiquinone cycle in enhancing univalent oxygen reduction has received particular focus. Excess ROS generation in cells can interfere with the function of tissues and organs, leading to a number of diseases or even the organism’s premature death (Sun et al., 2016). Complex II wasn’t considered to be a source of ROS in many tissues because succinate participates in reverse electron transfer, which is the mechanism by which electrons go from succinate to ubiquinone via complex II and back to complex I (Liu et al., 2002; Yankovskaya et al., 2003). However, complex II alterations that occur with tissue aging have been considered as the origin of O2•− production (Ishii et al., 2011), it was suggested that a mutation in complex II might also result in O2•− overproduction (Ishii et al., 2005). Additionally, Paddenberg et al in 2003 evaluated how mitochondrial complex II contributes to the production of ROS and found that it is essential in hypoxic conditions. Complex II catalytic activity changes from succinate dehydrogenase to fumarate reductase in reduced oxygen tension, and this change is linked to an increase in ROS production (Paddenberg et al., 2003). According to reports, respiratory chain production of ROS is controlled by the transmembrane electric potential (Korshunov et al., 1998), in contrast to others who offered evidence that the production of ROS and mitochondrial polarization are not related (Shabalina and Nedergaard, 2011).

Nonenzymatic glycosyl chemistry theory

According to this theory, aging of skin cells is influenced by internal factors such as nonenzymatic glycosylation, glycosylation induced crosslinking damage to proteins is the primary cause of aging. Advanced glycation end products (AGEs) are produced by the nonenzymatic glycosylation process, which involves free reducing sugars and free amino groups of proteins, DNA, and lipids. The accumulation of AGEs will impact cellular homeostasis and protein structure changes, leading to aging and darkening of skin (Zheng et al., 2022). The active carbonyl groups of reducing sugars and the free amines of proteins, lipids, and nucleic acids participate in a sequence of chemical events that result in non-enzymatic glycation. AGEs can damage numerous organs and create a risk to human health because they generate ROS, aberrant proteins or growth factors that alter the integrity of the extracellular matrix (ECM), and release pro-inflammatory cytokines (Zong et al., 2011; Khan et al., 2019). AGEs interact with receptors of advanced glycation end products (RAGE) through a process called the AGE–RAGE axis. This interaction triggers a chain of events and intracellular signaling pathways that regulate the inflammatory response, autophagy, proliferation, and apoptosis (Prasad and Mishra, 2018). Another theory states that AGEs can change the structure and mechanical characteristics of tissues by cross-linking lipids and ECM proteins. Furthermore, AGEs can increase the generation of ROS, oxidative stress, and mitochondrial dysfunction (Chen and Guo, 2021). Glycation inactivates the antioxidant enzymes themselves, increasing the damage from oxidative stress (Fournet et al., 2018). There are potential substrates for AGE formation, including lipids, nucleic acids, and extracellular matrix components found in connective tissue. The development of certain illnesses is greatly affected by the dysregulation of cellular physiology and cellular signaling pathways based on AGE accumulation, which modifies protein molecular structure as well as the functioning and activity of enzymes and receptors (Ottum and Mistry, 2015). Moreover, AGEs promote the production of pro-inflammatory chemicals such as cytokines, chemokines, and acute-phase proteins by inducing oxidative stress and triggering a number of stress-induced transcription factors, such as the nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and signal transducer and transcriptional activator (STAT) pathways (Chung et al., 2009).

Significant alterations in the biomechanical properties of tissues, such as stiffness and decreased regeneration, are linked to human aging. These changes are especially important for tissues that are rich in ECM components and long-lived proteins, such as skeletal muscle, tendons, joints, bone, the heart, arteries, the lungs, skin, and the lens (Roy et al., 2015). Since the rate of protein turnover is thought to be a determining factor in the development of AGE, glycation alters long-lived proteins such as collagen. Furthermore, the basement membrane is greatly impacted by inflammation caused by elevated AGE levels because it increases the levels of inflammatory cytokines such as TNF-α and IL-1β (Striker and Striker, 1996). By stimulating the production of ECM proteins, they also heighten inflammatory responses on a local and global level. AGE covalently cross-links to the ECM to reduce its flexibility and resistance to hydrolytic destruction of collagen or elastin (Greenwald, 2007). The basement membrane then starts to thicken. The mechanical characteristics of tissues, particularly the vasculature, are impacted by these modifications (Yang et al., 1991; Politz et al., 2002). Ultraviolet (UV) radiation and smoking accelerate the aging process of the skin, promote the synthesis of AGEs, and cause them to accumulate in tissues, including the skin (Biskanaki, 2023). Because AGEs link to collagen and elastic fibers, they make the skin less elastic and more rigid. This phenomenon is mostly caused by modifications in the production of the ECM components and the enzymes that cause ECM turnover (Fournet et al., 2018).

DNA damage/Repair theory

According to this theory, aging and genomic instability are aggravated by unrepaired DNA damage. DNA breaks, cross-links and altered bases are examples of age-related DNA damage, though the specific DNA lesions that cause aging are still up for argument. This theory is a component of the broader theory that a general loss of molecular integrity causes aging (Hayflick, 2007). Because the sources of harm also grow with age, DNA damage increases as well. Oxidative stress (OS) brought on by ROS alters a number of biomolecules and is one of the primary causes of cumulative damage to biomolecules, including DNA. Furthermore, it has been suggested that as people age, their ability to repair damaged DNA declines, resulting in mistakes during replication or repair that cause mutations such as base substitutions, tiny insertions or deletions, and chromosome rearrangements. As a result, somatic mutations are a reliable molecular indicator of genomic instability and DNA damage (Neidernhefer et al., 2018). Cell phenotypes linked to aging, such as senescence or mortality, can result from unrepaired DNA damage, which can also cause genomic instability and signaling cascades (Rodier et al., 2009). In fact, it is believed that as cells age, their ability to repair DNA damage decreases (Maynard et al., 2015).

Mitochondrial aging theory

In 1972, Harman created the mitochondrial theory of aging, which included the idea that mtDNA mutations may represent the primary cause of the mitochondrial dysfunction observed in aging to the free radical theory of aging (Harman, 1972). The energetic capacity of an individual is determined throughout their lifespan by their inherited nuclear and mtDNA (Wallace, 2008). Aging-related somatic mtDNA mutation accumulation results in a decline in mitochondrial function. Organ failure is the outcome of cellular loss brought on by the ensuing decrease in energy capacity, rise in oxidative damage, and rise in apoptosis. Age-related increases in mtDNA mutations are known to be directly related to the generation of ROS in the mitochondria (Cortopassi and Amheim, 199٠). The shape, dynamics, and function of mitochondria are all altered in senescent cells. Defects in mitochondrial oxidative phosphorylation (OXPHOS), for instance, are seen during the early phases of cellular senescence (Lafargue et al., 2017). Reduced mitochondrial membrane potential, increased proton leakage, and increased ROS generation are all consequences of cellular senescence (Lee et al., 2006), thus enhancing DNA damage. Moreover, cells undergoing senescence display altered mitochondrial metabolite homeostasis (Correia-Melo and Passos, 2017). Senescent cells mitochondria show significant morphological and dynamic changes in addition to functional modifications. A dysfunctional mitochondrial network results from the upregulation of mitochondrial biogenesis during senescence. Through mitochondrial fission and fusion events, this network is essential for cells to meet their metabolic demands (Mohammed et al., 2020a; Dawood et al., 2023; Alghetaa et al., 2023a). According to Wallace et al. (2010), mitochondria are becoming increasingly important in metabolic disorders, neurodegeneration, and aging. While oxidative phosphorylation (OXPHOS) is the primary mechanism by which this dynamic organelle produces ATP, mitochondria are also involved in biomolecule production, death, and calcium control. The intricate and conserved maintenance processes emphasize the significance of mitochondria. These consist of autophagy, mtDNA repair, and redox regulation. Furthermore, the life of an organism depends on the transcription, translation, and replication of mtDNA as well as the appropriate operation of OXPHOS. Superoxide, a ROS that functions as a signaling molecule and a source of damage, is mostly produced by mitochondria. Aerobic organisms have an antioxidant defense mechanism that uses enzymes like catalase and superoxide dismutase to eliminate ROS (Ventura-Clapier et al., 2008).

Cell membrane theory

Healthy cell membrane function is essential to all cellular processes. Thus, it is reasonable to propose that alterations in the integrity and composition of the cell membrane may be linked to aging features. According to this belief, the lipid composition of the cell membrane has an important influence on aging. Unsaturated fatty acids and their metabolites are essential for both the aging process and processes occurring outside of cells, suggesting that the lipid composition of the membrane changes as people age and vice versa. Therefore, alterations in the membrane lipid composition determine how cells function and age. Because each type of cell has a unique membrane makeup, this explains why the aging process varies through cells, tissues and organs (Manjari and Das, 2000; Mohan and Das, 2001). Examining the phospholipid fatty acid composition of the rat’s liver, kidney, and heart at 3, 12, and 24 months of age demonstrated that saturated fatty acids did not change significantly with age and the liver and heart linoleic acid (LA; 18: 2 n−6) and the kidney gamma-linolenic acid (DGLA; 20: 3 n−6) significantly decreased. This is in addition to the fact that the amounts of unsaturated fatty acids change with age, and this depends on the kind of cell or tissue (Das, 2021).

Cell theory

The aging of cells is a complex process with many moving components. First, cell’s shape changes, as with aging they get flatter and larger. This change is seen in both healthy cells and malignant cells growing in vitro. Another indicator of cellular aging is increased activity of the lysosomal enzyme beta-d-galactosidase. It is the most prominent and commonly used cellular aging indicator (Kurz et al., 2000). Another change associated with aging is increased cell granularity, which is connected to an increase in lysosome mass in older cells (Lee et al., 2006). As cells age, they undergo a variety of changes related to the proteins that comprise the cytoskeleton. As people age, their levels of the protein’s tubulin and β-actin change (Nishio and Inoue, 2005). Aging causes DNA demethylation, which appears in different cell and tissue types. In vitro-grown cells showed a reduction in demethylation levels as the number of passes increased. The aging process involves hypomethylation in addition to DNA demethylation and the demethylation of certain genes, including MYC and β-actin. The p16INK4a gene is one of the genes that is hypomethylated as people age, the DNA methylation profile of aged fibroblasts and neoplastic cells was identical (Issa, 1999).

Telomeres theory

Telomeres are DNA and protein structures that are located at the ends of the chromosomes of eukaryotic cells. They shield against genetic information loss and chromosomal end degradation (Oeseburg et al., 2010). They are in control of a nucleus spatial organization, controlling the activity of gene transcription in sub telomere regions and allowing the repair mechanisms to distinguish between healthy and damaged chromosomal ends (Prescott et al., 2012). The length and structure of telomeres vary depending on the organism, organ, species, and even a single chromosome (Stewart et al., 2012). The tandem repeats of the sequence (5’-TTAGGG-3’) in the double-stranded cytosine-rich DNA, which is between 10 and 20 bp long, and the single-stranded guanine-rich DNA, which is between 50 and 300 nucleotides long, make up human telomeres (Aida et al., 2014). Every replication cycle shortens the telomeres of somatic cells. This occurrence results from the end of DNA natural replicating mechanism (Armanios and Blckburn, 2012). Telomere length decreases with age, typically by 26 base pairs per year, the shorter and faster the telomeres are shortened, the faster the organism ages. As an indication of aging, short telomeres can be seen as a signal to stop continuous cell division and apoptosis (Friedrich et al., 2000). The lifespan of an organism is affected by the so-called Hayflick limit, which regulates the maximum number of cell divisions that each cell can undergo. Because telomeres function as molecular clocks, a cell lifespan is vital. The feature of a species is the Hayflick limit, which corresponds to divisions in the terms of humans (Hayflick, 1965). Cells are thought to naturally minimize genetic instability by aging and dividing only a limited number of times. Also, most immune cells undergo changes in growth and biological activity as we age, which results in weakened resistance to infections, ineffective vaccinations, and the ineffective killing of altered cells. Certain recognized alterations, such as thymic atrophy and modifications in the makeup of T lymphocytes, can restrict immune cell activity to antigens of pathologically altered own cells (Mohammed et al., ٢٠٢٠; Alghetaa et al., 2023; Ahmed and Mohammed, 2022; Al-Khaqani and Mohammed, 2024; Elias and Mohammed, 2024).

Normal changes related to aging

Aging is a complex natural process that affects individuals differently and becomes more pronounced with advancing age. While some physiological changes can be significant, many are part of the normal aging process and can be managed effectively. These changes have been interpreted through various aging theories, either independently or in combination. The impacts of aging on key organs such as the lungs and kidneys are illustrated in Figure 1.

Pulmonary system

Peoples lungs alter in structure and function as they age. The lung’s primary functional respiratory components are the airways, the first one ends at the entrance and exit the alveoli, the second one starts at the alveoli having a capillary network for gas exchange. The number of alveoli, alveolar ducts, and capillary segments remains constant at adulthood. While alveolar size and alveolar-capillary surface area greatly increase with aging, compensatory remodeling-related changes in alveolar depth and acinar airway lumen are linked to advanced age (Quirk et al., 2016). As people age, their lung elastic recoil decreases because the surface tension forces created by their larger individual alveolar diameters decrease, increasing the end-expiratory lung volume (Babb and Rodarte, 2000). Alveolar ducts become enlarged due to modifications in the coiling structure of elastin and other fibers surrounding them, which results in an equally distributed increase in alveolar size without causing damage to the alveolar wall (Turner et al., 1968). Smaller airways close at larger lung volumes due to a decrease in elastic recoil, a decrease in the number of elastic attachments of supporting alveoli, and an increase in collagen (Verbeken et al., 1992). As a result, during normal tidal breathing, older adults may have narrower or closed airways, increase their functional residual capacity and decrease their expiratory outflow from the lungs (Kerstjens et al., 1997). The ability to remove mucus or foreign particles from the lungs can also be affected by significant changes in respiratory muscle strength and chest wall function, as age-related decreases in elastic recoil are not consistent throughout the lung. The structure of the thorax can affect lung function because of age-related changes in thoracic position and overall rib stiffening (Enright et al., 1994). As people age, their functional residual capacity increases due to changes in chest wall deformation and a decrease in the lungs elastic recoil (Polkey et al., 1997). Person’s ages of lungs decrease in respiratory muscle and diaphragm strength (Tolep et al., 1995). A smaller chest cavity can occur from curvature of the spine and reduced space between the ribs caused by narrowing of the intervertebral disk space. Age does not significantly change overall lung capacity, despite a decline in elastic recoil brought on by weakened respiratory muscles and lower chest wall compliance (Sharma and Goodwin, 2006). Age-related changes in the respiratory system, such as alterations in the thoracic cage and lung parenchyma, abnormal lung function, including abnormalities in ventilation and gas exchange, decreased exercise capacity, impairment of the airway nerve, and decreased respiratory muscle strength and elasticity, all have an impact on the cough reflex, sneezing, and breathing (Schneider et al., 2021). Lung function declines and immune responses are compromised as a result of these gradual alterations (Haynes, 2020). The lung mucosa that surrounds the alveolus is composed of up of the alveolar lining fluid (ALF), an aqueous hypo phase, and a surfactant lipid layer. Lung-resident cells depend on a proper homeostatic balance of stress response and related inflammatory pathways to avoid excessive damage (Torrelles and Schlesinger, 2017). Maintaining good lung function is the primary purpose of the naturally soluble components in ALF (Torrelles and Schlesinger, 2017). According to other research, older humans and mice lung tissue have prominent levels of oxidative stress and basal inflammation. These conditions can cause vital cellular and innate soluble components to malfunction and increase the host’s exposure to respiratory diseases and infections like TB, influenza, and pneumonia (Harpur et al., 2021). Determining the timing and mechanism of these cellular and molecular changes is essential to understanding aging in general and age-related lung-specific illnesses in particular. Higher levels of TNF-α, IL-6, IL-1β, and IL-12, as well as decreased lung protein function and protein oxidation more carbonyl and nitro tyrosine-containing proteins, indicators of oxidation by reactive oxygen (ROS) and nitrogen (RNS) species, respectively, are baseline indicators of inflammation in older adults, according to Moliva et al. (2019).

Renal system

Aging is characterized by a gradual decline in physiological integrity and cellular function in numerous organ systems, which can result in conditions like diabetes, cancer, heart disease, and neurodegenerative diseases (Lopez-Otín et al., 2013). During the normal aging process, many changes in the kidney’s structure and physiological function are reported. Degeneration from age-related illnesses and natural aging can significantly speed up functional decline and perhaps increase a patient’s risk of acute kidney injury. Normal aging kidney changes differ from fatigued kidney changes, even though they can occur with the same diseases (Dybiec et al., 2022). Numerous factors can contribute to the aging kidney’s response to its the surrounding area, such as telomere shortening, which causes senescence with age, klotho signaling, which shortens lifespan, Wnt signaling, which is linked to organ fibrosis in the context of injury or disease, decreased antioxidant capacity, which increases stress and renal injury, fibrosis, which causes nephrosclerosis, poor renal perfusion, and is a risk factor for developing comorbidities like hypertensive renal disease, senescence or arrest of the G1 phase of the cell cycle, which leads to an increase in senescent renal cells as we age, and vascular changes, such as increased renovascular tone and stiffening, which causes comorbidities like hypertension (Reyes-Farias and Carrasco-Pozo, 2019). The aging kidney is linked to a number of functional, clinical, microscopic, and macroscopic alterations. It has been demonstrated that kidney mass decreases between the ages of 30 and 80, with the drop being noticeably more pronounced after the age of 50 (Ray and Reddy, 2023). Reduced mass, weight, and length, as well as an increase in cysts and calcification, are examples of macroscopic alterations (Randles et al., 2021). The volume of renal parenchyma declined with age in a number of image and autopsy studies of older persons, with no comorbidities found (Glassock and Rule, 2012). Examples of these functional changes include decreased renal blood flow, sodium resorption, tubule transport, glomerular filtration rate, acidification due to issues with the acid-base balance, renin synthesis from organs involved in the renin-angiotensin aldosterone system, and the ability to concentrate or dilute urine. Atrophy in the number and quality of tubules, fibrosis, thickening of the artery walls, and scarring of the glomeruli that filter urine are examples of microscopic changes (Dybiec et al., ٢٠٢٢).

D-galactose and aging

Galactose is a C-4 epimer of glucose, meaning it differs from glucose in the configuration at only one carbon atom, specifically the fourth carbon. Louis Pasteur discovered galactose in milk for the first time in 1856 and called it lactose. It was only later given the name galactose, derived from the Greek word galakt, meaning milk. When galactose joins with glucose, it forms lactose, a disaccharide commonly found in milk. Galactose exists in two enantiomeric forms, D-galactose and L-galactose, but D-galactose is the primary form found in nature (Acosta and Gross, 1995). Galactose appears to be particularly important for mammals since the main carbohydrate in milk (lactose) is made up of one molecule of galactose connected to one molecule of glucose by the β−1→4 glycosidic bond. The fact that galactose still makes up the majority of milk sugar in some cases when lactose is not the primary milk carbohydrate such as in sea lions and marsupials, indicates that it is crucial for the early stages of postnatal development (Homolak et al., 2024). Like most sugars, galactose is a naturally occurring aldohexose that is more commonly found in nature in its D-configuration (Bell, 1962). Galactose is available as free or bound, and it forms the disaccharide lactose, a sugar present in most animal milks and a key source of energy in infants (Georgi et al., 2013). Tomatoes, Brussels sprouts, bananas, and apples are among the fruits and vegetables that contain free galactose, while milk and dairy products are their main natural source (Kim et al., 2007). Additionally, biscuits, sweets, and different dairy foods with a high galactose content have made extensive use of lactose hydrolysate syrup as a sweetener (Acosta and Gross, 1995). Additionally, biscuits, confections, and various dairy sweets with high monosaccharide galactose content have frequently used lactose hydrolysate syrup as a sweetener (Cheng et al., 2020). The production of heparin/heparan sulfates and the galactosylation of ceramide during the Schwann cell myelin sheath synthesis (PNS process) are two of the several physiological processes that depend on galactose (Coelho et al., 2015). In human cells, galactose is known to be spontaneously generated. A male adult weighing 70 kg may generate up to 2 grams of galactose daily (Berrry et al., 1995). In general, the lysosomal hydrolysis of galactose-containing glycoproteins, glycolipids, and proteoglycans is a potential reaction mechanism for endogenous galactose production. Galactosemia is caused by two factors: a higher consumption of foods high in galactose or metabolic abnormalities due to genetic mutations in the Leloir pathway enzymes (Lai et al., 2009). Using an animal model (rat, rabbit, mice) of D-gal, numerous research had been conducted to evaluate the aging mechanisms of the heart and brain (Cai et al., 2022; Pantiya et al., 2023). D-gal could also be used to simulate liver aging, according to other results (Azman et al., 2021; Altamemi et al., 2024).

D-galactose and oxidative stress

D-galactose enhanced aging models (rat, rabbit, mice) development in a dose and time-dependent manner (Zhu et al., 2022; Zhang et al., 2023). D-galactose induces cellular senescence associated with pathological disorders leading to aging due to an increase in the production of ROS (Homolak et al., 2024; Peng et al., 2023). There are several harmful effects of D-galactose and its oxidative metabolites on cells. Galactose oxidase can oxidize D-galactose to produce hydrogen peroxide (H2O2) and reactive aldehydes (Hsieh et al., 2009). OH radicals are known to be produced by H2O2, primarily through Fenton reactions, and are notorious for their direct impact on the oxidation of proteins, lipids, and DNA (Davies, 2016). The production of galactitol by aldose reductase is another fate for D-galactose. Due to its ability to induce osmotic stress, galactitol can increase electrolyte and metabolite imbalances (Ansari and Dash 2012; Golubev et al., 2017). Additionally, Schif’s base products, also known as Amadori products, are unstable substances that undergo many reactions over days to become more stable compounds. D-galactose attaches to amino group molecules to create these compounds (Shwe et al., 2018). Within months or years, the stable Amadori products undergo a permanent alteration to become AGE product molecules (Hsieh et al., 2009). Cognitive impairment and cell death result from increased production of ROS and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase when AGE products interact with their receptor-advanced glycation end product (Hsieh et al., 2009). Animals given D-galactose developed accelerated aging processes, resulting in symptoms similar to aging (de Almeida et al., 2021; Wang et al., 2022). Through nonenzymatic glycation, D-gal reacts with free amine of amino acids in proteins to produce advanced glycation end products that may aid in the formation of ROS through D-gal oxidative metabolism and glycation end products (Pasupulati et al., 2024). Research suggests that D-gal can cause rat brain oxidative injuries by overexpression of two primary aging-related processes, including aging markers (p53, p21), apoptotic markers (Bax and CASP3), and accumulation of β-galactosidase, leading to significant neurodegenerative effects (El-Far et al., 2021, 2022, 2024; Saafan et al., 2023). Li et al., (2016) findings regarding the accumulation of β-galactosidase in the aged rat hippocampus are indeed noteworthy. β-galactosidase is an enzyme that is typically associated with lysosomal function. Its increased levels in the brain have been linked to several age-related processes including lysosomal dysfunction leading to the accumulation of cellular debris and impaired clearance of damaged components (Guerrero-Navarro et al., 2022) causing cellular senescence and neurodegeneration, also increased levels of β-galactosidase enzyme might contribute to the activation of immune cells and the release of inflammatory mediators (Sikora et al., 2021), which can damage brain tissue, and accumulation of β-galactosidase in the hippocampus could suggest impaired protein clearance, which is a hallmark of neurodegenerative diseases such as Alzheimer’s disease (Greenwood and Brown, 2021; Liu, 2022; Kitchener et al., 2024). D-galactose caused an increase of mutations in the brain mitochondrial DNA (Farajdokht et al., 2021) by lowering enzymes that repair DNA (Chen et al., 2011). Damage to mitochondrial structures caused by frequent deletions of mitochondrial DNA (Du et al., 2015). By inducing oxidative stress and mitochondrial dysfunction in the hippocampus, cerebral cortex, auditory cortex, and ventral cochlear nucleus, among other brain regions, D-galactose can accelerate the aging process of the brain (Long et al., 2007).

Yin et al. (2009) cumulative evidence suggested that oxidative stress is the main potential etiology of many cellular injuries, mitochondrial dysfunction, and DNA damage, which contribute to neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease (Dash et al., 2025). In conclusion, elevated ROS levels are likely to cause cellular senescence (Liguori et al., 2018). The exact mechanism by which oxidative stress causes aging is unknown. Increasing alveolar size and decreasing elastic recoil are the two main ways that aging influences the lungs; this may promote airway closure and raise residual volume (Azman and Zakaria, 2019). Lung elastic composition was changed as a result of the D-galactose therapy (Hadzi-Petrushev et al., 2015), D-galactose therapy has been shown to decrease the quantities of antioxidant enzymes such as CAT, NOS, GSH-Px, and SOD in lung tissues while increasing oxidative indicators such as MDA and NO (Lei et al., 2016). Administration of D-galactose significantly lowers the liver’s total antioxidant capacity (T-AOC) as well as the mRNA synthesis of NADPH quinone dehydrogenase 1 (NQO1) and heme oxygenase-1 (HO-1). This leads to oxidative stress (Azman and Zakaria, 2021; Al-Kurdy, 2020). As people normally age, changes to the spine, muscles, and ribs over time impact normal lung function, and kyphosis or curvature of the spine occurs, causing a decrease in the space between the ribs and creating a smaller chest cavity (Sharma and Goodwin, 2006). A slight anterior curvature in the thoracic spine is normal in humans and referred to as hyper kyphosis with an angle greater than 40 degrees, which represents the 95th percentile of normal, but the rate of kyphosis progression does indeed accelerate after the age of 40, and this tendency is more pronounced in women than in men, which is often attributed to several factors, including osteoporosis, hormonal changes and posture and lifestyle (Ensrud et al., 1997). Besides, age-related changes in muscle function can also contribute to the development and progression of hyperkyphosis. The overall muscle strength and function decline by about 2% per year with age. This loss of muscle mass and strength, known as sarcopenia, can have several implications for spinal health (Brown and Hasser,1996). As people age, their inspiratory and expiratory respiratory muscles become weaker. This weakness of the respiratory muscles can lead to decreased lung capacity, a decreased ability to breathe in response to increasing demands, and a decrease in mitochondrial adenosine triphosphate (ATP) reserves to support an abrupt increase in metabolic demand. As a result, respiratory infections are more likely to occur and breathing effort is elevated (Nagano et al., 2021). The ability of the lungs to clear mucus is crucial for maintaining respiratory health, through coughing, cilia moving mucus upward, and the body ability to capture and remove particles from the airways. However, aging can decrease and impair lung mucus clearance via two mechanisms, including reduced cough strength, a decline in elastic recoil, and alterations in particle clearance. There are many factors can contribute to these changes such as muscle atrophy, decreased immune function associated with altered bronchoalveolar lavage fluid composition and cilia in the airways may become less effective in moving mucus upward with age, leading to increased mucus buildup (Cho and Stout-Delgado, 2020; Cho, 2023), thus decreasing the lungs expiratory outflow and raising the functional residual capacity (Janssens et al., 1999) may lead to lung parenchymal damage and impairing gas exchange.

Exposure to D-galactose accelerates the aging processes by triggering oxidative stress biomarkers in the kidney tissues and reducing total antioxidant capacity (Azman and Zakaria, 2019). Furthermore, rats given D-galactose had significantly lower levels of total thiol groups (T-SH) and protein thiol groups in their renal tissues, as well as significantly higher amounts of lipid hydroperoxides (LHP) and 8-OHdG, than the young control group (Liu et al., 2010). Treatment with D-galactose significantly raised blood urea nitrogen, creatinine (Cr), cystatin C, and uric acid levels; these results indicate that D-galactose treatment may cause kidney injury, as revealed by the elevated levels of these markers (Fan et al., 2016).

Garcia-Trejo et al. (2024) demonstrated that D-galactose increases the generation of ROS in the proximal tubule cell lines of the human kidney 2 (HK2) and the pig kidney 1 (LL-PK1) in Lilly Laboratories. Galactose reductase and galactose oxidase metabolism of D-galactose as a result of cells being exposed to an oxidizing environment (Azman and Zakaria, 2019; Homolak, 2023), associated with an increase in ROS and 8-OHDG levels with no effect on the activities of antioxidant enzymes as CAT and SOD in LLC-PK1 cells, but a decrease in CAT activity in HK-2 cells (Garcia-Trejo et al., 2024). Moreover, indicators of senescent cells include larger and irregularly shaped nuclei. Loss of Lamin B1, increased actin fiber creation that clumps up in the cytoplasm and nucleus, cell cycle arrest in the G1/G2 phase, and forcing the cells to flatten can all result in these changes (Heckenbach et al., 2022; Huang et al., 2022; Belhadj et al., 2023; Princilly et al., 2023). Previously, it was mentioned that D-galactose treatment can induce DNA damage through the increased production of ROS. This DNA damage can lead to the loss of epigenetic information and mutagenesis (Aird et al., 2013). The aging-related pathways of insulin-like growth factor 1 (IGF-1), Wingless-related integration site (Wnt), transforming growth factor β (TGF-β), and nuclear factor kappa B (NF-κB) are inhibited by the Klotho protein, which is primarily produced in the brain, kidneys, pancreas, and other tissues. These pathways have the ability to cause fibrosis, neoplasia, inflammation, immunological dysfunction, cellular senescence, and apoptosis. Therefore, Klotho protein may be involved in the regulation of cellular senescence and age-related diseases and may play a role in preventing cellular senescence. Thus, a decrease in Klotho protein is associated with an increase in the expression of proteins associated with senescence, such as p16, p21, and p53 (Miao et al., 2021). On the other hand, Klotho protein may protect cells from oxidative damage by enhancing the activity of CAT and SOD enzymes through transcription factor Nrf2 and FoxO (Donate-Correa et al., 2023; Yu et al., 2023). Klotho overexpression changes to reduce the formation of O2• while klotho deficiency increases ROS production and enhances oxidative stress according to a significant amount of research (Ashrafizadeh et al., 2020; Miao et al., 2021; Prud’homme et al., 2022). Induced aging animals’ model by D-gal modulates multiple mechanisms to facilitate the cardiovascular aging process by causing mitochondrial disorders, oxidative stress, and reducing bioenergetics (Sahu et al., 2024). It has been found that administration of D-galactose led to decreased levels of total antioxidant capacity (Dehghani et al., 2019).

Moreover, D-galactose raises the weights of the whole heart and left ventricle, a condition linked to hypertrophy and aging (Chen et al., 2018). Additionally, D-gal-treated animal heart tissues showed fuzzy structure, twisted shortening, and plumping of cardiac muscle fibers. The interval and congestion of myocardial interstitial capillaries were also significantly expanded (Lei et al., 2016).

How D-Galactose induces aging in different organs/systems

D-galactose is a typical model of aging; it has been used experimentally as a tool to achieve model of accelerate aging many years ago (Azman and Zakaria, 2019).

D-galactose is a monosaccharide that has been extensively studied for its potential to induce accelerated aging, being used as a consolidated methodology for studies in various organs and tissues. It is often used as a model to investigate the mechanisms of aging, the exact mechanisms by which D-galactose induces aging through various molecular mechanisms are not fully understood. To get a better understanding of aging and to prevent its effects on many organs/ systems, D-galactose was used to artificially create aging in animal models and was summarized in Table 1.

Table 1: Effects of D-galactose on body organs.

Organs /System	Effects of D-Galactose	References
Brain	D-galactose can cause the brain's accelerated aging process, which includes damaged mitochondrial structure, decreased ATP production, increased mitochondrial DNA mutation, apoptosis, enhanced oxidative stress, neuronal degeneration, and increased aberrant gene expression.	Kaviani et al., 2017; Shwe et al., 2018; Ullah et al., 2015
Lung	D-galactose-induced lung aging through its effects on antioxidant systems, mitochondrial biogenesis, autophagy, and apoptosis via SIRT1, P53/caspase3 and down regulating the FOX1 signaling pathways. Loss of alveolar elasticity caused by aging primarily reduces the lung's capacity to expand by decreasing its elastic recoil, which may facilitate airway closure and increase residual volume. D-gal caused oxidant/antioxidant-related lung damage, including alveolar wall breakdown and inflammatory infiltration.	Lei et al., 2016; Ji et al., 2017; Azman and Zakaria, 2019; Kumar et al., 2022; Salama et al., 2023
Kidney	Increased renal function tests BUN, creatinine, uric acid and Cystatin -C, and alkaline phosphatase while Ca+2 decreased. Down-regulated the expression of Klotho mRNA and Nrf2 signaling pathway in kidney tissue, while Akt1 and FOXO3a were significantly increased.	Zheng, 2020; Chu et al., 2017; Pan et al., 2021
Reproductive system (erectile dysfunction)	D-galactose induces their effects on sexual behavior through an increase in β-galactosidase activity via an increase in oxidative stress, loss of erectile components, and increased cell senescence.	Cho et al., 2018; Angulo et al., 2019; Jing et al., 2019; de Almeida Rezende, 2021.
Liver	Redox imbalance. liver injury was associated with inflammation, and especially the excessive expression of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6). Also induced activation of TLR4/MAPK/NF-κB pathways. A significant decrease in the expression levels of PI3K and Akt in the liver significantly decreased the expression of anti-apoptotic protein Bcl-2 and increased the expression of pro-apoptotic protein Bax. Change in protein expression of Microtubule-associated proteins 1A/1B light chain 3B (LC3-II/LC3-I) ratio. Increasing liver mitochondrial failure with decreased efficiency of mitochondrial biogenesis.	Jing et al., 2019 Saleh et al., 2019; Li et al., 2020; Azman et al., 2021; Habieb et al., 2021; Ma et al., 2023; Lee et al., 2023; Far et al., 2024; Somasundaram et al., 2024
Heart	Aging increases the risk development of coronary heart disease (CHD) related to overproduction of ROS. Aging decrease total antioxidant capacity. Hypertrophy of left ventricle. Increase weight of whole heart. myocardial interstitial capillary vessel congestion, twisted shortening, and distension of heart muscle fiber.	Bo-Htay et al., 2018; Dehghani et al., 2018

Advanced glycation end products (AGEs) and aging

Nonenzymatic glycation produces advanced glycation end products, or AGEs, which are potentially dangerous heterogeneous molecules of irreversible chemicals. The reducing sugar’s reactive carbonyl group interacts with lipids, proteins, or nucleic acids in non-enzymatic glycation reactions. Both healthy and unhealthy states may generate AGEs either naturally or with the help of outside sources (Twarda-Clapa et al., 2022). It appears AGEs have pathological effects that include changes to the structure and function of proteins, cellular dysfunction and apoptosis, and eventually injuries to various tissues and organs because they can produce reactive oxygen (ROS) and nitrogen (RNS) species, oxidative stress, and inflammation (Sharma et al., 2020, Santos et al., 2024). Numerous aging-related diseases, including diabetes, cardiovascular disease, kidney dysfunction, osteoporosis, cancer, neurodegenerative diseases, and liver disorders, have been linked to the development and progression of crosslinks created by AGEs interactions with their cell surface receptors for advanced glycation end products (RAGEs) (Fishman et al., 2018; Gasparotto et al., 2018; Dariya and Nagaraju, 2020). Endogenous AGEs are adducts produced and progressively accumulated in the body due to inflammation, oxidative stress, and hyperglycemia, all of which are commonly observed in metabolic syndromes such as diabetes (Rhee et al., 2018). A free amino group, such as adenine or guanine in nucleic acids or the N-terminus, lysine, or arginine residue in proteins, joins forces with the carbonyl group of a reducing sugar to generate AGEs in a process called a nonenzymatic glycation reaction or Maillard reaction. A highly reversible nucleophilic addition mechanism that produces a reversible Schiff base adduct following this reaction. After that, this adduct is placed to create hemoglobin A1c, a more stable and covalently bound Amadori product. The Amadori product subsequently undergoes irreversible chemical changes in the body including oxidation, dehydration, and rearrangement to produce AGEs. In addition to nonenzymatic glycation, AGEs can also be generated by the polyol pathway and lipid peroxidation with or without hyperglycemia, depending on the substrate type, reactant amount, exposure time, and host cellular context (Aragano and Mastrocola, 2017; Rungratanawanich et al., 2021). AGE development is promoted by a variety of conditions. These include cigarette smoking or raised alcohol use, eating a lot of processed food, renal status, homeostatic imbalance, inflammation, hyperglycemia, and oxidative stress. Furthermore, AGE activation can raise oxidative stress, and increased oxidative stress can function as a catalyst to promote AGE formation, leading in a mutually beneficial cycle that speeds up pathophysiological conditions (Henning and Glomb, 2016). Change to cigarette smoke and foods and beverages that contain high fructose corn syrup, such as soft drinks, are examples of exogenous AGEs. Furthermore, food preparation may result in the production of dietary AGEs. Temperature, water volume, pH level, cooking duration, and cooking method (frying, broiling, or long-term cooking or storage) are some of the variables that affect the development of dietary AGEs. These changes trigger off the nonenzymatic Maillard reaction, which produces AGEs and glycation products (Zhao et al., 2019). High heat and long cooking times increase the amount and rate of AGE formation in diets (Lund and Ray, 2017). AGEs are increased in foods with high pH values (up to 10) because of free amino groups in an alkaline environment (Nowotny et al., 2018). Modern Western diets that include cheese, meat prepared using a dry-heat method, breakfast cereals, and cooked foods are thought to contain dietary AGEs (Delgado-Andrade, 2016). Reactive glycation products which are contained in cigarette smoke in addition to dietary AGEs, have been shown to enhance AGE accumulation in smoker’s tissues and blood (Cerami et al., 1997). AGEs originating from external sources are typically far more prevalent than those originating from internal sources. Because exogenous and endogenous AGEs have similar biological functions and can cause oxidative stress, inflammation, and cellular damage all of which contribute to harmful pathophysiology, consuming foods and beverages high in exogenous AGEs is probably going to present more health risks than consuming AGEs produced endogenously (Zhang et al., 2009, Van Dongen et al., 2022).

Conclusions

Aging is a global issue that affects people on a daily basis, the significance of senescence treatment alternatives is increasing. In this review, the most important organ in the aging process and the most sensitive organ is the brain. Many theories, such as genetics, evolution, and metaphysics, attempt to explain how organisms age. Dependency develops more quickly in elderly people due to age-related cognitive impairment, toxin accumulation, cellular senescence, and metabolic damage. The outcome is most likely the result of combining these theories. The role of mitochondria is linked to mimetic aging caused by D-galactose. Excess exogenous supplementation of d-galactose (d-gal), a monosaccharide and reducing sugar, generates reactive oxygen species (ROS), leading to cell damage and death. ROS accumulation is critical in aging. Therefore, d-gal-induced aging mouse models are used in aging studies. Moreover, we suggest that further investigations are needed to explore the biological changes during the aging process that could affect other organs, such as the cardiovascular system compartments, as well as endocrinological responses. It is also worth recommending the use of D-galactose as an aging enhancer in lab animals for aging-related research.

Acknowledgment

Not applicable.

Novelty Statement

This research article provides deep insight into the physiological roles of aging process in modulation of vital organs function such as lungs and kidneys.

Author’s Contribution

BA and AM design, conceptualization, review the draft and last version of this manuscript.

BS wrote the draft, revised and wrote the last version of this manuscript.

BA, AM, BS and NA have reviewed and approved the submitted version of the manuscript.

Abbreviations

AGEs, Advanced glycation end products; ALF, Alveolar lining fluid; ATP, Adenosine triphosphate; CAT; Catalase; Cr, Creatinine; D-Gal, D-Galactose; ECM, Extracellular matrix; GLA, gamma-linolenic acid; HK2, Human kidney 2; IGF-1, Insulin-like growth factor-1; IL-12, Interleukin-12; IL-1B, Interleukin-1beta; IL-6, Interleukin-6; LA, Linoleic acid; LHP, lipid hydroperoxides; MAPK, mitogen-activated protein kinase; mRNA, Messenger RNA; mtDNA, mitochondria DNA; NF-κB, nuclear factor kappa B; NQO1, NADPH quinone dehydrogenase 1; OXPHES, Oxidative phosphorylation; RAGEs, Receptors Advanced glycation end products; ROS, Reactive oxygen species; SOD, Superoxide dismutase; STAT, Signal transducer and transcriptional activator; T-AOC, Total antioxidant capacity; TGF-β, transforming growth factor β; TNF-α, Tumor necrosis factor-α; Wnt,Wingless-related integration site.

Data availability

The data is available from the corresponding author in reasonable request.

Generative AI and AI-assisted technology statement

The authors of this article declare that neither generative artificial intelligence nor AI-assisted technology were used in the creation of this publication or its data.

Conflict of interest

The authors have declared no conflict of interest.

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