Begoña Zapatería 1 and Esperanza Arias 1,2* 1Department of Medicine (Marion Bessin Liver Research Center), Department of Pathology

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 4 journals. Those papers have been cited 74 times in total.

Supporting evidence — 4 representative gaps

• c-Jun N-terminal kinase signaling in aging (2024) · Frontiers in Aging Neuroscience · cited 12× · doi

  The JNK signaling pathway plays a significant role in the aging process. Activation of JNK signaling triggers the release of inflammatory factors from cellular pyroptosis, leading to alterations in cellular communication and fibrosis. JNK activation induces macrophage senescence and promotes senescence and programmed cell death in neural progenitor cells (NPCs). In Drosophila, JNK activation promotes the progression of Parkinson’s disease through disruption of the brain-gut axis and intestinal barrier. Additionally, in the absence of BMAL1, p-JNK levels increase in osteoblasts, resulting in impaired osteoclast differentiation and mineralization, which contributes to osteoporosis. Moreover, elevated JNK activity in hairless mice further accelerates skin aging. Notably, dysregulation of the circadian rhythm protein PER2 activates the AP-1 transcription factor via the JNK pathway, contributing to age-related thyroid hyperplasia. Furthermore, JNK activation inhibits the transcriptional activity of the Cx43 gene promoter, leading to decreased Cx43 expression and impaired intercellular communication, which can contribute to atrial fibrillation and cardiovascular disease. Activation of JNK reduces hTERT activity and disrupts Shelterin structure, resulting in telomere shortening in leukemia KG1 cells, as well as inducing G1 phase arrest and apoptosis in HL-60 cells. However, under the influence of elevated plasma irisin levels, JNK activation increases stem cell telomerase activity and lengthens telomeres. Activation of JNK signaling promotes the activation of the NLRP3 pathway, leading to GSDMD-mediated cellular pyroptosis, further contributing to the development of atherosclerosis, systemic sclerosis, and myocardial fibrosis. Finally, several JNK-targeting drugs, including CEP-1347, CC-930, CC-90001, and AGI-1067, have already reached the clinical stage. Additionally, natural compounds such as nypa fruticans extract and quercetin have shown promising results in animal models and isolated experiments (Figure 8). Currently, the main limitation of JNK intervention in anti-aging drugs lies in the fact that JNK is a central hub in multiple signaling pathways. Inhibiting JNK alone may lead to various adverse reactions within cells. While positive results have been observed in in vitro experiments, clinical trials have shown some side effects, including hepatotoxicity and cardiac discomfort. Therefore, the concentration and dosage of JNK intervention drugs that can achieve the desired anti-aging effect, as well as the need for adjuvants, require extensive experimentation for verification. To fully utilize JNK intervention drugs, it is important to achieve a dual role in promoting senescence-related pathways and inhibiting anti-aging pathways. For example, these drugs could promote

  generalfuture work
  Keywords: activation aging drugs signaling cells activity pathway cellular leading senescence promotes intervention anti pathways role
• Mechanistic and Therapeutic Insights into Nrf2-Mediated Redox Regulation in Periodontitis (2026) · Antioxidants · cited 5× · doi

  Periodontitis is driven by persistent oxidative stress and dysregulated inflammatory signaling, in which impaired Nrf2 activity contributes to tissue destruction and alveolar bone loss. Activation of the Nrf2 pathway restores the antioxidant capacity, suppresses NF-κB- and NLRP3-mediated inflammation, and promotes osteogenic repair, positioning Nrf2 as an important regulatory node linking redox imbalance and bone remodeling. Nev- ertheless, whether Nrf2 dysfunction represents a primary driver of disease progression https://doi.org/10.3390/antiox15010072 Antioxidants 2026, 15, 72 19 of 27 or a secondary consequence of chronic inflammation and microbial dysbiosis remains incompletely understood. Further, the translation of Nrf2-targeted strategies into clinical care remains limited. Future work should prioritize standardized dosing and optimized delivery systems. In particular, nanoparticle- or hydrogel-based sustained-release formula- tions should be evaluated in preclinical and clinical models. Integrating Nrf2 modulation with metabolic control, microbiome regulation, and personalized therapeutic approaches may enable precision host-modulatory therapy. Although antioxidant toothpastes con- taining polyphenolic or herbal compounds have demonstrated anti-inflammatory effects in experimental periodontal models, direct evidence linking these formulations to Nrf2 pathway activation in periodontal tissues is currently lacking. Addressing the variability across experimental models and the paucity of human interventional data will be critical for clarifying the therapeutic scope of Nrf2-centered strategies. Advancing these strategies through rigorously designed preclinical and clinical studies will be essential to fully realize the therapeutic potential of Nrf2-centered interventions in periodontal and systemic health. Author Contributions: Conceptualization, S.W.; writing—original draft preparation, S.W.; writing— review and editing, H.N., Y.S., Y.Y., M.H., E.M. and N.D.; supervision, S.W. All authors have read and agreed to the published version of the manuscript. Funding: This research was supported by the Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science. (21K10199). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: No new data were created or analyzed in this study. Data sharing is not applicable to this article. Conflicts of Interest: The authors declare no conflicts of interest.

  generalfuture work
  Keywords: strategies clinical models therapeutic periodontal statement applicable inflammatory bone activation pathway antioxidant inflammation linking remains
• Proteostasis Decline and Redox Imbalance in Age-Related Diseases: The Therapeutic Potential of NRF2 (2025) · Biomolecules · cited 46× · doi

  The relationship between proteostasis and NRF2 is pivotal in understanding the aging process. In young healthy cells, NRF2 helps in maintaining proteostasis by promoting the expression of genes involved in OS management, proteasomal degradation, and autophagy. However, as cells age, NRF2 activity declines, weakening the cellular response to oxidative damage and protein misfolding. The diminished NRF2 function accelerates the progression of age-related disorders (e.g., neurodegenerative and cardiovascular diseases), which are driven by OS, inflammation, and proteostasis failure. Therefore, the interplay between proteostasis and NRF2 is critical for determining the rate of cellular aging and the onset of age-associated dysfunctions (Figure 2). Therapeutic strategies that target the NRF2 pathway and restore protein homeostasis hold promise for delaying aging and mitigating age-related diseases. One approach is the activation of NRF2 through small molecules like SFN, which can enhance the expression of NRF2 target genes involved in detoxification, antioxidant production, and proteostasis regulation. Another strategy involves the use of proteostasis regulators, such as chaperones, proteasome or autophagy inducers, to restore protein homeostasis and prevent the aggregation of damaged proteins. Due to the multifactorial nature of aging-related diseases, combination therapies that target both NRF2 activation and proteostasis regulation could provide synergistic benefits. Gene therapy and CRISPR-based approaches targeting the NRF2 pathway or key components of proteostasis may also emerge as future treatments to enhance cellular resilience against aging. Biomolecules 2025, 15, 113 23 of 38 However, the dual role of NRF2 highlights the need for careful therapeutic targeting, and further studies are required to fine-tune these interventions, ensuring their safety and efficacy in promoting healthy aging while avoiding potential side effects. Therefore, it is critical to develop therapeutics that precisely modulate NRF2 activity without triggering adverse effects, such as uncontrolled cell proliferation, which can arise from excessive NRF2 activation. Similarly, chronic enhancement of proteostasis mecha- nisms must be carefully controlled to avoid disruptions in normal cellular processes. In this scenario, while NRF2 and proteostasis-based therapies hold great promise, several challenges remain. Indeed, despite preclinical studies that have shown promise in targeting NRF2 and proteostasis in age-related disorders, translating these findings into clinical ther- apies remains a challenge. Further research is needed to optimize drug delivery, minimize side effects, and understand the long-term effects of NRF2 activation. Nevertheless, the absence of NRF2 would negatively influence the NRF2-KEAP1 pathway, resulting in a diminished defense against oxidative or electrophilic stress. To optimize the activation of this pathway, it is beneficial to identify a balance between a maximally tolerated dose, which serves as a threshold before toxicity occurs, and a biologically effective dose that effectively activates the pathway to combat stress. By carefully determining this balance, we can enhance the pathway’s protective functions. Nevertheless, these approaches rep- resent a promising therapeutic avenue for enhancing cellular resilience during aging and combating major age-related diseases. Author Contributions: Conceptualization, B.B. and F.D.D.; Methodology, B.B., A.T., A.I.R., N.C., S.S., A.B., L.G., J.P.M., E.P., S.D., A.D., A.C. and F.D.D.; Writing—review and editing, B.B., A.T., A.I.R., N.C., S.S., A.B., L.G., J.P.M., E.P., S.D., A.D., A.C. and F.D.D.; Validation, B.B. and F.D.D.; Supervision, B.B.; Funding acquisition, B.B., A.C. and F.D.D. All authors have read and agreed to the published version of the manuscript. Funding: Research in the authors’ laboratories is funded as follows: A.I.R. and A.C. by the Span- ish Ministry of Science, Innovation, and Universities (PID2019-110061RB-I00, PID-2021-122766OB- 100, PDC2021-121421-I00, PDC2022-133765-I00), CIBERNED/ISCIII (CB06/05/0010), and The Au- tonomous Community of Madrid (P2022/BMD-7230). F.D.D. by a Fondi Ateneo grant from Sapienza University (nos. RM12117A2EC1C9E4, RM11916B78D5711A, and RG1181642744DF59) and by the Jerome Lejeune Foundation (no. 2280_2023b). Data Availability Statement: No new data were created or analyzed in this study. Acknowledgments: The collaboration of the authors was supported by European COST Action CA20121: Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases (BenBedPhar). Webpage: https://benbedphar.org/about-benbedphar/ (accessed on 25 November 2024). Conflicts of Interest: The authors declare no conflicts of interest.

  generalfuture work
  Keywords: proteostasis aging pathway cellular related diseases activation effects authors protein therapeutic target promise enhance regulation
• Aging, cancer, and autophagy: connections and therapeutic perspectives (2025) · Frontiers in Molecular Biosciences · cited 11× · doi

  Begoña Zapatería 1 and Esperanza Arias 1,2* 1Department of Medicine (Marion Bessin Liver Research Center), Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States, 2Einstein Aging Research Center, Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY, United States Aging and cancer are intricately linked through shared molecular processes that influence both the onset of malignancy and the progression of age- related decline. As organisms age, cellular stress, genomic instability, and an accumulation of senescent cells create a pro-inflammatory environment conducive to cancer development. Autophagy, a cellular process responsible for degrading and recycling damaged components, plays a pivotal role in this relationship. While autophagy acts as a tumor-suppressive mechanism by preventing the accumulation of damaged organelles and proteins, cancer cells often exploit it to survive under conditions of metabolic stress and treatment resistance. The interplay between aging, cancer, and autophagy reveals key insights into tumorigenesis, cellular senescence, and proteostasis dysfunction. This review explores the molecular connections between these processes, emphasizing the potential for autophagy-targeted therapies as strategies that could be further explored in both aging and cancer treatment. Understanding the dual roles of autophagy in suppressing and promoting cancer offers promising avenues for therapeutic interventions aimed at improving outcomes for elderly cancer patients while addressing age-related deterioration. KEYWORDS aging, cancer, autopaghy, proteostasis, therapeutics

  generalfuture work
  Keywords: cancer aging autophagy einstein medicine center cellular department albert college bronx united states molecular processes

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