Aging represents an intricate biological phenomenon, resulting in a marked reduction in the homeostasis of tissues and organs, the functionality of organisms, their stress resilience, and regenerative capabilities (Aman et al., 2021). It also adheres to the inherent natural order of life. Based on statistics; by 2050, 20 % of the world's population will be over 65 years old, indicating an escalating trend of population aging (Dogra et al., 2022). Aging has been demonstrated as the primary risk factor for aging-related diseases (Li et al., 2019); including Alzheimer's disease (AD), diabetes mellitus, Parkinson's disease (PD), atherosclerosis, intestinal inflammation, age-related macular degeneration, and osteoarthritis, which typically exhibit age-dependent manifestations (Santoro et al., 2021). AD is a neurodegenerative disease that usually manifests in old age and is one of the most common forms of dementia. Aging is a major factor in AD onset (Gonzales et al., 2022); with reported incidence rates of AD almost doubling every 5 years after the age of 65 (Cummings, 2018). Based on estimates from international AD organizations; as of 2018; approximately 50 million patients had dementia worldwide, which is expected to triple by 2050 (Scheltens et al., 2021). AD and other aging-related diseases often co-occur; a phenomenon referred to as comorbidity. Common comorbidities of AD include cardiovascular diseases (Levine et al., 2023); diabetes mellitus (Mancinetti et al., 2023); depression (Marawi et al., 2023); PD (Tripathi and Kumar, 2023); gastrointestinal disorders (Jiang et al., 2023); and osteoarthritis (Du et al., 2023). These comorbidities may interact; increasing the complexity and therapeutic challenges for patients (Surguchov, 2020). Numerous prospective epidemiological studies have delved into the connection between DM and AD; with the majority categorizing diabetes mellitus as a risk factor for AD (Gudala et al., 2013). Research has also revealed that alterations in the ecological balance of the gut microbiota occur before the onset of AD symptoms; suggesting that these changes can serve as early indicators of AD (Ferreiro et al., 2023). Gut microbes modulate AD pathology and cognitive deficits through polyunsaturated fatty acid-related neuroinflammation (Chen et al., 2022). Furthermore; osteoarthritis may affect AD pathophysiology through mechanisms such as the activation of central pain processing pathways; central nervous system hypersensitivity, and inflammation (Innes and Sambamoorthi, 2020). AD and PD are two of the most prevalent neurodegenerative diseases. Research reports indicate that during PD progression; approximately 30–40 % of patients will develop dementia symptoms, a condition known as PD with dementia. Moreover, in populations with PD lasting more than 10 years, at least 60 % of individuals ultimately progress to PD with dementia (Wood et al., 2016).

Activating transcription factor 4 (ATF4) features a basic region leucine zipper (bZip) structure and belongs to the ATF/cAMP response element-binding protein (CREB) family. ATF4 is a gene promoter within cells, which activates a transcriptional program that governs genes involved in reduction of oxidative stress, amino acid biosynthesis, and induction of autophagy (Jiang et al., 2019). It may also be associated with the rate of aging; longevity, and tumorigenesis (Cui et al., 2021). Simultaneously; ATF4 has garnered attention in the field of neuropathology, where it has been strongly associated with neurodegenerative diseases such as AD, PD, and amyotrophic lateral sclerosis, as well as behaviors related to drug addiction and memory formation (Korneeva, 2022). Considering the unique role of ATF4 as a key molecule in the integrated stress response of the endoplasmic reticulum (ER) and several age-related diseases, the modulation of ATF4 expression may represent a promising avenue for the treatment of these conditions. Here, we provide a comprehensive review of the biological functions of ATF4, its mechanisms of action in age-related diseases, and preclinical research findings on the regulation of ATF4 for the treatment of these diseases. This review aims to enhance our understanding of the potential therapeutic strategies involving ATF4 in age-related diseases. Fig. 1 demonstrates the potential therapeutic effects of ATF4 in aging-related diseases. Table 1 presents alterations in ATF4 in patients with aging-related diseases.