Senolytic drugs: from discovery to translation

Kirkland, James L.; Tchkonia, Tamar

doi:10.1111/joim.13141

Cited by 685 publications

(677 citation statements)

References 147 publications

(234 reference statements)

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“…ABT 263 (Navitoclax) is a chemotherapy drug that is used to induce apoptosis in cervical, esophageal, leukemia, and lung cancer cells by inhibiting the antiapoptotic proteins, Bcl-2 and Bcl-xL [35][36][37][38]. ABT 263 was shown to selectively clear senescent cells in vivo through inhibition of Bcl proteins [39-41] and to diminish SASP [42].…”

Section: Resultsmentioning

confidence: 99%

Plasma dilution improves cognition and attenuates neuroinflammation in old mice

Mehdipour

Skinner

et al. 2020

GeroScience

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Our recent study has established that young blood factors are not causal, nor necessary, for the systemic rejuvenation of mammalian tissues. Instead, a procedure referred to as neutral blood exchange (NBE) that resets signaling milieu to a pro-regenerative state through dilution of old plasma, enhanced the health and repair of the muscle and liver, and promoted better hippocampal neurogenesis in 2-year-old mice (Mehdipour et al., Aging 12:8790–8819, 2020). Here we expand the rejuvenative phenotypes of NBE, focusing on the brain. Namely, our results demonstrate that old mice perform much better in novel object and novel texture (whisker discrimination) tests after a single NBE, which is accompanied by reduced neuroinflammation (less-activated CD68+ microglia). Evidence against attenuation/dilution of peripheral senescence-associated secretory phenotype (SASP) as the main mechanism behind NBE was that the senolytic ABT 263 had limited effects on neuroinflammation and did not enhance hippocampal neurogenesis in the old mice. Interestingly, peripherally acting ABT 263 and NBE both diminished SA-βGal signal in the old brain, demonstrating that peripheral senescence propagates to the brain, but NBE was more robustly rejuvenative than ABT 263, suggesting that rejuvenation was not simply by reducing senescence. Explaining the mechanism of the positive effects of NBE on the brain, our comparative proteomics analysis demonstrated that dilution of old blood plasma yields an increase in the determinants of brain maintenance and repair in mice and in people. These findings confirm the paradigm of rejuvenation through dilution of age-elevated systemic factors and extrapolate it to brain health and function.

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Section: Resultsmentioning

confidence: 99%

Plasma dilution improves cognition and attenuates neuroinflammation in old mice

Mehdipour

Skinner

et al. 2020

GeroScience

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“…However, time-dependent accumulation of senescent cells, likely through decreased immunoclearance, occurs in virtually all vertebrates ( Jeyapalan et al, 2007 ; Liu et al, 2009 ) and has been definitively shown to drive aging ( Baker et al, 2016 ), rather than simply occur with aging. Senescent cells also contribute to age-related diseases such as atherosclerosis ( Roos et al, 2016 ), osteoporosis ( Chandra et al, 2020 ), nonalcoholic fatty liver disease ( Ogrodnik et al, 2017 ), cancer ( Alimirah et al, 2020 ), neurodegenerative diseases ( Chinta et al, 2018 ; Zhang et al, 2019 ), and numerous other age-related conditions ( Kirkland and Tchkonia, 2020 ). Interestingly, NF-κB is the transcription factor that is most activated with aging ( Adler et al, 2007 ).…”

Section: Cellular Senescence and The Secretory Phenotypementioning

confidence: 99%

DNA damage—how and why we age?

Yousefzadeh

Henpita

Vyas

et al. 2021

eLife

267

200

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Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, to increased risk of morbidity and mortality. Many factors contribute to aging, such as the time-dependent accumulation of macromolecular damage, including DNA damage. The integrity of the nuclear genome is essential for cellular, tissue, and organismal health. DNA damage is a constant threat because nucleic acids are chemically unstable under physiological conditions and vulnerable to attack by endogenous and environmental factors. To combat this, all organisms possess highly conserved mechanisms to detect and repair DNA damage. Persistent DNA damage (genotoxic stress) triggers signaling cascades that drive cells into apoptosis or senescence to avoid replicating a damaged genome. The drawback is that these cancer avoidance mechanisms promote aging. Here, we review evidence that DNA damage plays a causal role in aging. We also provide evidence that genotoxic stress is linked to other cellular processes implicated as drivers of aging, including mitochondrial and metabolic dysfunction, altered proteostasis and inflammation. These links between damage to the genetic code and other pillars of aging support the notion that DNA damage could be the root of aging.

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“…The relevance of senescence in some pathogenic conditions has led to the development of senolytics, compounds able to selectively eliminate senescent cells [ 63 ], as potential treatments for several diseases [ 64 , 65 , 66 ]. Since senescence may alter (upregulate or downmodulate) the replication capacity of different viruses, it is important to evaluate the effect of drugs with senolytic activities on virus replication.…”

Section: Virus and Senescencementioning

confidence: 99%

The Interaction of Viruses with the Cellular Senescence Response

Seoane

Vidal

Bouzaher

et al. 2020

Biology

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Cellular senescence is viewed as a mechanism to prevent malignant transformation, but when it is chronic, as occurs in age-related diseases, it may have adverse effects on cancer. Therefore, targeting senescent cells is a novel therapeutic strategy against senescence-associated diseases. In addition to its role in cancer protection, cellular senescence is also considered a mechanism to control virus replication. Both interferon treatment and some viral infections can trigger cellular senescence as a way to restrict virus replication. However, activation of the cellular senescence program is linked to the alteration of different pathways, which can be exploited by some viruses to improve their replication. It is, therefore, important to understand the potential impact of senolytic agents on viral propagation. Here we focus on the relationship between virus and cellular senescence and the reported effects of senolytic compounds on virus replication.

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Senolytic drugs: from discovery to translation

Abstract: Content List-Read more articles from the symposium: "Cardiovascular program and cardiovascular retreat".

Cited by 685 publications

References 147 publications

Plasma dilution improves cognition and attenuates neuroinflammation in old mice

Plasma dilution improves cognition and attenuates neuroinflammation in old mice

DNA damage—how and why we age?

The Interaction of Viruses with the Cellular Senescence Response

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