In this section, we will review some commonly used mouse models of accelerated systemic aging including drug treatment, genetic engineered models, irradiation induction, etc. They are characterized by an aging phenotype in multiple tissues or organs, reflecting systemic aging. The systemic-induced accelerated aging mouse models are summarized in Table 1.

Type	Subdivision	Phenotypes
D-galactose-induced senescence model	Brain	Cognitive impairment Mitochondrial dysfunction Neuronal degeneration Apoptosis Depressive and anxious
	Heart	Cardiac fibrosis Collagen accumulation Fibroblasts disordered arrangement
	Kidney	Kidney index ↓ Uric acid & Cys-C ↑ Glomerular and tubular damage ↑
	Liver	Liver fibrosis Glycogen levels ↓ Lipid deposition ↑
	Reproductive system	Estrogen and progesterone ↓ Ovarian follicle regression Uterine wall endometrial gland atrophy Disrupt estrous cycles
	Intestinal flora	Disturbance
	Lung	Oxidative stress ↑ Fibrotic status Chronic inflammation
SAMP mice	SAMP 1	Aging amyloidosis Immune dysfunction Renal atrophy Hearing loss Senile pulmonary hyperinflation
	SAMP 6	Senile osteoporosis Myeloid progenitor cell senescence
	SAMP 8	Astrogliosis Microgliosis Neurodegeneration Amyloid accumulation MAPT hyperphosphorylation
	SAMP 10	Learning and memory impairment Cerebral cortex and limbic system atrophy
Rps9 D95N mouse		Altered fur Cataracts Hunched posture Body composition function & body weight ↓ Fat mass & muscle strength ↓ Shortened lifespan Mouse urinary syndrome Extramedullary hematopoiesis
	Lama−/−	Short lifespan Growth retardation Muscular dystrophy Altered lipid metabolism
	Wrn∆hel/∆hel	Short lifespan Abnormal hyaluronic acid excretion Metabolic abnormalities Increased genomic instability and cancer incidence
	Csa−/−, Csb−/−	Short lifespan Reduced fat mass Photoreceptor cell loss Neural pathology
Progeria syndrome mouse	XpdTTD/TTD	Short lifespan Trichothiodystrophy
	Bub1bH/H, Xpg−/−	Brain atrophy Neuronal loss Neurofibrillary deposition of Aβ or senile plaques
	Bub1bH/H, Bub1b+/GTTA	Mean muscle fiber diameter ↓ Muscle fiber size variation ↑ Intermuscular fibrosis Regenerative capacity of skeletal muscles ↓
Mitochondrial DNA polymerase mutant mouse		Lifespan ↓ Weight loss Subcutaneous fat ↓ Hair loss Kyphosis Osteoporosis Anemia Fertility ↓ Spermatogonia depletion Heart enlargement
Total body irradiation (TBI) model		Progressive premature frailty Cognitive decline Whole blood antioxidant capacity ↓ RBC glutathione ↓ Thymic involution Articular cartilage and bone degeneration Ovarian environment damage
Ozone-induced senescence model		Cognitive decline Memory impairment AD symptoms Lung tumor growth ↑
Chronic jet-lag mouse		Accelerated initial tumor growth Shortened mouse survival Induce spontaneous hepatocellular carcinoma Obesity Depression Addiction Abnormal cardiac structure Impaired cardiac function

D-galactose is a common aldohexose that exists naturally in the body and in daily foods [8]. After ingestion, a healthy adult can metabolize and eliminate a maximum daily dose of 50 g of galactose from the body within about eight hours [9]. However, when galactose accumulates to high levels, reactive oxygen species (ROS) are generated by mitochondrial respiratory chain enzymes, xanthine oxidase, lipoxygenase, cyclooxygenase, nitric oxide synthase, and peroxidase. Increased ROS can subsequently lead to elevated oxidative stress and inflammation, inducing mitochondrial dysfunction and apoptosis [10]. Meanwhile, the elevated mitochondrial ROS level can lead to the activation of many biochemical pathways, such as the polyol pathway, the formation of advanced glycation end products (AGEs), the activation of protein kinase C, and the hexosamine pathway [11,12]. Overall, D-galactose-induced methods can increase aging markers such as AGEs, receptors for advanced glycation end products (RAGEs), aldose reductase (AR), sorbitol dehydrogenase (SDH), decreased telomerase activity, shortened telomere, β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), amyloid β (Aβ), aging-related pathways (p16, p21, p53, etc.), and positive senescence-associated β-galactosidase (SA-β-gal) staining [13]. Multiple tissues and organs, including the brain, heart, lung, liver, kidney, reproductive system, gastrointestinal system, and so on, manifest aging phenotypes after D-galactose treatment [14].

Previous works have shown that D-galactose induces brain aging by increasing mitochondrial dysfunction, oxidative stress, inflammation, apoptosis, and decreasing the expression of brain-derived neurotrophic factor. D-galactose injections may induce brain aging similar to human brain aging in many ways, including mitochondrial dysfunction, increased oxidative stress, decreased ATP production, neuronal degeneration and apoptosis, and cognitive deficits [13,15,16,17]. D-galactose increases the neuro-inflammation markers via activating NF-κB, leading to memory impairment [18,19]. Besides learning and memory inhibition, D-galactose-treated mice also exhibit depressive and anxious behaviors [20].

The leading cause of death in elderly people worldwide is cardiovascular disease [21]. D-galactose treatment increases the risk of cardiovascular disease, which is associated with excess ROS and oxidative stress. Persistent oxidative stress has been revealed to be related to decreased ferric reducing antioxidant power and lower activity of Cu-Zn superoxide dismutase, leading to myocardial damage [22]. Studies have shown that galactose reduces endogenous hydrogen sulphide producing enzyme cystathionine γ-lyase (CSE) [23] and antioxidant enzymes such as catalase (CAT), haem oxygenase-1 (HO-1), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and nitric oxide synthase (NOS), leading to decreased total antioxidant capacity and inducing lipid peroxidation markers including malondialdehyde (MDA), lipid hydroperoxides (L-OOH), and conjugated dienes (CD) in cardiac tissue [24,25]. D-galactose increases whole heart weight and left ventricle weight, which is associated with hypertension and aging. At the same time, the heart tissue showed enlarged myocardial fibers, blurred structure, shortened distortion, widening of the interval, and obvious capillaries of myocardial interstitial congestion [26]. D-galactose treatment resulted in cardiac fibrosis, significant accumulated collagen, and disordered arrangement of fibroblasts compared with the control. D-galactose also increased cardiac apoptosis markers [27]. Excessive D-galactose can be transformed to advanced AGEs via the Maillard reaction [28]. AGEs bind to the receptors, RAGE, increasing ROS production via NADPH oxidase. NADPH oxidase further activates p38 MAP kinases, causing transcription factor NF-κB translocating into the nucleus, where transcription of inflammatory cascades like tumor necrosis factor alpha (TNF-α) are enhanced [29]. D-galactose treatment can also increase fibrotic markers such as connective tissue growth factor (CTGF), transforming growth factor β1 (TGF-β1), phosphorylated mitogen-activated protein kinase 1/2 (p-MEK1/2), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), matrix metalloproteinase (MMP), and pathological specific protein 1 (SP1) [30].

D-galactose treatment also increases oxidative markers (e.g., MDA) and decreases antioxidant enzymes (e.g., SOD, GSH-Px and NOS) in lung, liver, and renal tissues [26,31,32,33,34,35]. D-galactose treatment can affect lung elastic constitution. The primary effects of treatment on the lungs are increased alveolar size and reduced elastic recoil, which may facilitate airway closure [36]. D-galactose treatment is considered to successfully mimic the natural aging process by increasing oxidative stress, fibrotic status, and chronic inflammation in the lungs.

The liver is the main site where D-galactose is metabolized, thus excess D-galactose in the body may significantly affect the liver. As previously mentioned, high levels of D-galactose can react with free amines in the amino acids to form AGEs, which is found to be involved in the progression of various liver diseases [12]. High levels of D-galactose lead to the accumulation of its final metabolite, galactitol, which will eventually lead to ROS accumulation through the p38 MAPK/NRF2/HO-1 signaling pathway and cause cellular osmotic stress in the liver [37]. D-galactose treatment significantly increased apoptotic proteins including Bax, procaspase-3, and caspase-3, and raised the ratio of Bax/Bcl-2 in the liver tissue [34,38,39]. Various changes similar to natural aging were also observed in the D-galactose-treated livers. Compared with controls, the livers of D-galactose-treated animals had lower levels of glycogen and more lipid deposition. Masson’s trichrome staining showed obvious collagen fibers around blood vessels and in the interphase of liver tissue, and irregular pseudo-lobules around liver tissue, indicating a state of liver fibrosis [40,41].

D-galactose treatment significantly reduced the renal index of animals, and markers of acute kidney injury such as uric acid and cystatin C (Cys-C) were also increased [42]. In the kidney, D-galactose administration resulted in an increase in the TUNEL-positive cells and DNA fragmentation. In addition, p21 expression and the staining intensity of SA-β-gal were also increased in kidney cells [43]. Extensive glomerular and tubular damages were detected in D-galactose-treated animals, as the number of tubules with cellular necrosis from the renal cortices and outer medulla were significantly increased [43,44].

In the male reproductive system, D-galactose induced oxidative stress, marked by an increase in MDA levels in the prostate, testis, epididymis, and decrease in SOD activity in the testis. Peroxidation in the testicular and epididymal mitochondrial fractions was also significantly increased after D-galactose treatment [45]. Female reproductive aging is characterized by decreased levels of estrogen, progesterone, inhibin B, anti-Müllerian hormone, and androgens, which include free testosterone, dehydroepiandrosterone (DHEAS), and androstenedione [46]. Compared to the control groups, D-galactose administration produced aging-associated changes like reduced estrogen and progesterone levels and increased FSH and luteinizing hormone (LH) levels. Ovarian follicle regression and atrophy on the uterine wall and endometrial gland were observed after D-galactose treatment, which indicates disrupted estrous cycles and damaged uterine and ovarian tissues [47].

D-galactose injection can lead to changes in the level of oxidative stress that affect the microbial environment in the intestine and lead to intestinal flora disorder [48]. The ecology of intestinal flora is closely related to aging, and intestinal ecological disturbance can lead to accelerated aging and a shortened lifespan [49]. Transferring gut microbiota from aged to young germ-free mice triggered innate immune and inflammatory responses. Effects of aging include increased differentiation of CD4⁺ T cells in the spleen, upregulation of intestinal inflammatory cytokine such as TNF-α, and increased cycling of bacterial-derived inflammatory cytokines [50,51]. In addition, D-galactose administration significantly decreased the small intestine propulsion rates and prolonged gastrointestinal transit time [49]. The aging gut triggers chronic inflammation, leading to gut dysplasia and intestinal dysplasia in turn leads to defective epithelial function, predisposing the host to infection, neoplasia, and increased mortality [52].

Researchers from Kyoto University found an aging phenotype from a subset of pups while maintaining an inbred line of AKR/J mice. Characteristics of these mice include hair loss, reduced activity, and a shortened lifespan. These aging traits are thought to develop as a result of elevated oxidative stress and are inherited by their offspring. Further, the accelerated aging mice were grouped into several distinct subtypes according to their phenotypes [53].

Senescence-accelerated mouse/prone (SAMP) is a group of inbred mouse strains that typically exhibit accelerated aging [54]. Meanwhile, since it shows various aging-related diseases similar to humans, such as aging amyloidosis, senile osteoporosis, learning/memory impairment, etc., in specific lines, it is widely used for aging research. Cellular senescence in various cell types, including astrocytes, endothelial cells, progenitor cells, retinal epithelial cells, and fibroblasts, was found in the aging SAMP mice [55,56,57]. SAMP mice exhibit an increase in ROS generated by mitochondria or other cellular sites, which not only causes damage to mitochondria, but also triggers degradation that leads to the aging outcome [58].

SAMP1 mice are characterized by aging amyloidosis, immune dysfunction, renal atrophy, hearing loss, and senile pulmonary hyperinflation [59,60]. The lifespan of the SAMP1 mice is about 40% shorter than senescence-accelerated resistant mice (SAMR1), and various signs of aging appear early in appearance.

The SAMP6 mice model is a senile osteoporosis model animal that tends to develop osteoporosis at an early stage with aging due to its low bone density in instar [61]. Bone marrow transplantation experiments have revealed that the cause of SAMP6 osteoporosis is abnormalities in bone marrow stem cells [62]. The incidence of spontaneous leg fractures due to osteoporosis is high in adult SAMP6 mice. Cellular senescence in myeloid progenitors disrupts their differentiation in favor of adipogenesis over osteogenesis. This mechanism is thought to contribute to low osteoblast activity and osteoporosis in SAMP6 mice and the elderly [61,63,64].

The SAMP8 mice develop age-associated deficits in learning and memory and also exhibit various age-related neuropathological changes similar to aging humans [65,66]. Neuropathological changes including astrogliosis, microgliosis, and neurodegeneration occur as early as five months of age [67]. SAMP8 mice also showed accumulated amyloid and age-related microtubule-associated protein tau (MAPT) hyperphosphorylation, as well as increased nitric oxide synthase activity, further demonstrating their feasibility as a brain aging model [68,69]. In addition, decreased activities in SOD, CAT, glutathione reductase, and GSH-Px, and increased activity in acyl-CoA oxidase were detected in SAMP8 mice at 1–12 months of age [70]. SAMP6 and SAMP8 mice also develop many other age-related diseases, including retinal degeneration, testosterone deficiency [71], myocardial fibrosis [72], and hepatic lipid deposition [73].

The SAMP10 mice exhibit learning and memory impairment with aging, and atrophy is observed in the cerebral cortex and limbic system, so it is considered to be a spontaneous model animal for aging and brain degeneration. The atrophy of the frontal cerebral cortex and olfactory bulb is marked in SAMP10 mice [74,75].

So far, more than ten strains of SAMP mice have been identified and widely used in aging studies, each of which can develop various age-related diseases such as renal fibrosis (shrinking of the kidneys), immune dysfunction, and degenerative joint disease like osteoarthritis (OA), etc.

Rps9 D95N is a ribosome ambiguity mutation that causes error-prone protein synthesis in mammalian ribosomes, resulting in increased error-prone translation. Rps9 D95N mutant mice exhibit features of accelerated aging, including morphological (altered fur, cataracts, and hunched posture), physiological (body composition and function, body weight, fat mass, and muscle strength), and pathological (shortened lifespan, mouse urinary syndrome and extramedullary hematopoiesis), which also complements and explains the link between accumulation of erroneous proteins resulting from protein mistranslation and individual aging [76].

Mouse models of progeria syndrome have emerged as an attractive tool for evaluating intervention strategies for unhealthy aging due to their short lifespan, relatively simple strategies by single gene deletion or mutation, and their strong phenotypic similarities to normal aging [7]. To understand important mechanisms of the aging process, progeria mice (Lmna^−/−, Wrn^{∆hel/∆hel}, Csa^−/− or Csb^−/−) from common progeria types such as Hutchinson-Gilford Progeria, Werner Syndrome, and Cockayne Syndrome are being widely used.

The most common phenotypes in mouse models of progeria can be observed in bones, joints, skin, nervous system, adipose tissue, skeletal muscle, cardiovascular system, liver, kidney, and the hematopoietic system. Less common lesions occur in the gonads, eyes, and occasionally in the gastrointestinal tract [77].

Some human progeria syndromes like Werner Syndrome exhibit osteoporosis. Current data from a mouse model of progeria indicate that senile osteoporosis is the result of reduced bone turnover and loss of bone mass due to defects in osteoblast progenitor cells, osteoblast differentiation, or osteoblast function [77]. Degenerative joint disease is another major symptom that affects the elderly. Mutation in the Xpd gene of nucleotide excision repair (NER) leads to a short lifespan, causing trichothiodystrophy (TTD) in humans. As expected, Xpd^TTD/TTD mice exhibited a significant decrease in subchondral bone plate thickness compared to that observed in wild-type mice. Surprisingly, female Xpd^TTD/TTD mice exhibited less cartilage damage and fewer lost articular cartilage, compared to WT females [78].

During the aging process, skeletal muscle was inevitably accompanied with a reduction in muscle mass, known as sarcopenia or age-related muscle atrophy, and macroscopic examination of sarcopenic mice will show weight loss and marked reduction in muscle mass. Sarcopenia is characterized by the loss of muscle fibers and smaller fiber cross-sectional area that is defined as fiber atrophy [79]. The progeria mouse model Bub1b^H/H and Bub1b^+/GTTA mice showed decreased mean muscle fiber diameter, increased myofiber size variation, increased intermuscular fibrosis, and impaired regenerative capacity in skeletal muscles [80].

Common brain aging diseases include Alzheimer’s disease (AD) and cognitive dysfunction syndrome. Brain atrophy, neuronal loss, neurofibrillary deposition of Aβ or senile plaques, intraneuronal tauopathies (neurofibrillary tangles, NFTs), cerebrovascular amyloid angiopathy, neuronal lipofuscinosis, vascular and meningeal calcification, decreased white matter integrity, and astrogliosis are common age-related neurological pathologies [81]. The brains of several mouse models of progeria show neurodegenerative changes at an early stage. Similar to age-related gliosis, Bub1b^H/H mice have increased numbers of astrocytes and microglia at one and five months of age, respectively. Additionally, Xpg^−/− mice developed more astrocytes and increased activation of microglia in the brain and spinal cord [82].

3. Tissue-, Organ-, or System-Specific Mouse Models of Aging-Related Diseases

3.1. Model of Aging Brain or Nerve System

3.2. Model of Aging Muscle

3.3. Model of Aging Heart