Compound combinations targeting longevity: Challenges and perspectives

Rybina, Olga Y.; Symonenko, Alexander V.; Pasyukova, Elena G.

doi:10.1016/j.arr.2023.101851

Cited by 10 publications

(4 citation statements)

References 163 publications

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“…However, among these thousands of compounds, only a few was proved to be effective. Besides, these interventions which target single molecular have significant deficiency due to neglecting the complexity for living systems (Rybina et al., 2023). Therefore, developing novel strategies to combat aging is still imminent.…”

Section: Introductionmentioning

confidence: 99%

Identification of prospective aging drug targets via Mendelian randomization analysis

Mao,

Li,

Xiao

2024

Aging Cell

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Aging represents a multifaceted process culminating in the deterioration of biological functions. Despite the introduction of numerous anti‐aging strategies, their therapeutic outcomes have often been less than optimal. Consequently, discovering new targets to mitigate aging effects is of critical importance. We applied Mendelian randomization (MR) to identify potential pharmacological targets against aging, drawing upon summary statistics from both the Decode and FinnGen cohorts, with further validation in an additional cohort. To address potential reverse causality, bidirectional MR analysis with Steiger filtering was utilized. Additionally, Bayesian co‐localization and phenotype scanning were implemented to investigate previous associations between genetic variants and traits. Summary‐data‐based Mendelian randomization (SMR) analysis was conducted to assess the impact of genetic variants on aging via their effects on protein expression. Additionally, mediation analysis was orchestrated to uncover potential intermediaries in these associations. Finally, we probed the systemic implications of drug‐target protein expression across diverse indications by MR‐PheWas analysis. Utilizing a Bonferroni‐corrected threshold, our MR examination identified 10 protein‐aging associations. Within this cohort of proteins, MST1, LCT, GMPR2, PSMB4, ECM1, EFEMP1, and ISLR2 appear to exacerbate aging risks, while MAX, B3GNT8, and USP8 may exert protective influences. None of these proteins displayed reverse causality except EFEMP1. Bayesian co‐localization inferred shared variants between aging and proteins such as B3GNT8 (rs11670143), ECM1 (rs61819393), and others listed. Mediator analysis pinpointed 1,5‐anhydroglucitol as a partial intermediary in the influence LCT exhibits on telomere length. Circulating proteins play a pivotal role in influencing the aging process, making them promising candidates for therapeutic intervention. The implications of these proteins in aging warrant further investigation in future clinical research.

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Section: Introductionmentioning

confidence: 99%

Identification of prospective aging drug targets via Mendelian randomization analysis

Mao,

Li,

Xiao

2024

Aging Cell

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“…Theoretically, cellular senescence is caused by diverse stimuli, for instance, telomere shorting, culture shock, DNA damages, and oncogene activation 3 . Interestingly, in the past decades, selectively killing senescent cells (termed as senolytics) has been demonstrated to be beneficial for age‐associated diseases and prolonging healthy lifespan in mice 4 . However, not enough specific markers to distinguish those “bad” senescent cells from others limit the development of such an exciting field.…”

Section: Introductionmentioning

confidence: 99%

“…3 Interestingly, in the past decades, selectively killing senescent cells (termed as senolytics) has been demonstrated to be beneficial for age-associated diseases and prolonging healthy lifespan in mice. 4 However, not enough specific markers to distinguish those "bad" senescent cells from others limit the development of such an exciting field. Notably, recent studies unveiled that intracellular calcium signaling extensively controls cellular senescence and aging.…”

Section: Introductionmentioning

confidence: 99%

Zinc finger protein ZBTB17 controls cellular senescence via interacting with nuclear receptor RXRA and its downstream calcium signaling

Wang,

Gao,

Luan

et al. 2023

The FASEB Journal

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Cellular senescence is broadly known as a stable cell cycle arrest accompanied by a senescence‐associated secretory phenotype (SASP). In the past decades, calcium signaling has emerged as a key mediator of cellular senescence. However, the transcriptional regulation of calcium signaling during cellular senescence remains partially understood. We have previously identified the nuclear receptor RXRA as a key senescence repressor through inhibiting the endoplasmic reticulum (ER) calcium release channel inositol 1,4,5‐trisphosphate receptor, type 2 (ITPR2) mediated intracellular calcium signaling. Nevertheless, as a transcriptional recruiter, the mechanism by which RXRA inhibits ITPR2 during cellular senescence remains unclear. Here we identified the zinc finger protein ZBTB17 can interact with RXRA. Interestingly, knockdown of ZBTB17 induces a cascade of RXRA‐dependent intracellular calcium signaling, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) accumulation, DNA damages, and ultimately cellular senescence. Moreover, the signaling and senescence phenotype induced by knocking down of ZBTB17 can also be abolished after silencing ITPR2. Altogether, our work provides a new mechanism controlling intracellular calcium signaling and cellular senescence and unveils novel insight toward the role of zinc finger proteins.

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“…There are compelling research studies with the potential for treating the aged. This could be combined drug, gene, and cell therapies [10,11]. Such therapies could be accommodated by regulatory bodies such as the FDA.…”

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confidence: 99%

What Could Explain Delay for Age-Reversal Clinical Trials?

Faloon

2024

IJTS

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This is a commentary article using data reported by the United States Drug Approval (FDA) system for clinical trials. The text surmised reasons for this delay. The data show continued delay to impact drugs reaching patients. Instead of increasing drug approval, the statistics showed a trend of increased numbers of drug on hold. The reason for these delays need to be evaluated, and perhaps to apply new technologies to evaluate the data.

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Compound combinations targeting longevity: Challenges and perspectives

Cited by 10 publications

References 163 publications

Identification of prospective aging drug targets via Mendelian randomization analysis

Identification of prospective aging drug targets via Mendelian randomization analysis

Zinc finger protein ZBTB17 controls cellular senescence via interacting with nuclear receptor RXRA and its downstream calcium signaling

What Could Explain Delay for Age-Reversal Clinical Trials?

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