The use of geroprotectors to prevent multimorbidity: Opportunities and challenges

Morsli, Samir; Bellantuono, Ilaria

doi:10.1016/j.mad.2020.111391

Cited by 11 publications

(7 citation statements)

References 132 publications

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“…The median extension of life span by Zol is in the same range of other geroprotectors including rapamycin, with Zol extending the median life span of females by 14%–18% when given from middle age. Rapamycin, one of the most studied geroprotectors, which positively affects the immune system in older patients by boosting their ability to improve flu vaccine responses ( 30 ) and also improves several health-span parameters in mice ( 31 ), increases life span by 9%–14% in female mice when fed late in life ( 32 ). A similar level of extension was shown in other studies testing rapamycin in Drosophila ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

Zoledronate Extends Health Span and Survival via the Mevalonate Pathway in a FOXO-dependent Manner

Chen

Cordero

Alqarni

et al. 2021

The Journals of Gerontology: Series A

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Over recent decades, increased longevity has not been paralleled by extended healthspan, resulting in more years spent with multiple diseases in older age. As such, interventions to improve healthspan are urgently required. Zoledronate is a nitrogen containing bisphosphonate, which inhibits the farnesyl pyrophosphate synthase (FPPS) enzyme, central to the mevalonate pathway. It is already used clinically to prevent fractures in osteoporotic patients, who have been reported to derive unexpected and unexplained survival benefits. Using Drosophila as a model we determined the effects of Zoledronate on lifespan, parameters of healthspan (climbing ability and intestinal dysplasia) and the ability to confer resistance to oxidative stress using a combination of genetically manipulated Drosophila strains and Western blotting. Our study shows that Zoledronate extended lifespan, improved climbing activity and reduced intestinal epithelial dysplasia and permeability with age. Mechanistic studies showed that Zoledronate conferred resistance to oxidative stress and reduced accumulation of X-ray-induced DNA damage via inhibition of FPPS. Moreover, Zoledronate was associated with inhibition of pAKT in the mTOR pathway downstream of the mevalonate pathway and required dFOXO for its action, both molecules associated with increased longevity. Taken together, our work indicates that Zoledronate, a drug already widely used to prevent osteoporosis and dosed only once a year, modulates important mechanisms of ageing. Its repurposing holds great promise as a treatment to improve healthspan.

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Section: Discussionmentioning

confidence: 99%

Zoledronate Extends Health Span and Survival via the Mevalonate Pathway in a FOXO-dependent Manner

Chen

Cordero

Alqarni

et al. 2021

The Journals of Gerontology: Series A

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“…They promise to promote health span of more than one organ system at the same time in animal models ( Figueira et al, 2016 ; Bellantuono, 2018 ). Studies in model organisms or retrospective studies in patients show that they can ameliorate tissue dysfunction and reduce the onset and severity of many diseases [reviewed in ( Morsli and Bellantuono, 2021 )]. Over 200 compounds have been classified as geroprotectors, each reported to slow ageing and/or extend lifespan in a variety of organisms ( geroprotectors.org ).…”

Section: Geroprotectorsmentioning

confidence: 99%

“…More recently Rapamycin has also been shown to inhibit the Senescence Associated Secretory Phenotype (SASP) ( Wang et al, 2017 ), composed of pro-inflammatory and tissue remodelling factors and secreted by senescent cells. Already in clinical use as an immunosuppressor, Rapamycin has been tested extensively in animal models of ageing and age-related diseases [reviewed in ( Morsli and Bellantuono, 2021 )]. An analogue of Rapamycin, RAD001, has been tested in clinical trials at a substantially lower dose to elicit geroprotective effects to delay immunosenescence with excellent tolerability ( Mannick et al, 2014 ; Mannick et al, 2018 ).…”

Section: Geroprotectorsmentioning

confidence: 99%

“…This includes inhibition of inflammation, reduction in DNA damage and inhibition of SASP ( Algire et al, 2012 ; Moiseeva et al, 2013 ; Ashabi et al, 2015 ). There are multiple evidence in animal models and retrospective human studies that metformin has positive effects on multiple age-related diseases [reviewed in ( Morsli and Bellantuono, 2021 )]. Indeed a clinical trial, using Metformin to extend survival and reduce the incidence of multiple diseases (the TAME study) has obtained FDA approval ( Barzilai et al, 2016 ).…”

Section: Geroprotectorsmentioning

confidence: 99%

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Geroprotectors and Skeletal Health: Beyond the Headlines

Rayson¹,

Boudiffa²,

Naveed³

et al. 2022

Front. Cell Dev. Biol.

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Osteoporosis and osteoarthritis are the most common age-related diseases of the musculoskeletal system. They are responsible for high level of healthcare use and are often associated with comorbidities. Mechanisms of ageing such as senescence, inflammation and autophagy are common drivers for both diseases and molecules targeting those mechanisms (geroprotectors) have potential to prevent both diseases and their co-morbidities. However, studies to test the efficacy of geroprotectors on bone and joints are scant. The limited studies available show promising results to prevent and reverse Osteoporosis-like disease. In contrast, the effects on the development of Osteoarthritis-like disease in ageing mice has been disappointing thus far. Here we review the literature and report novel data on the effect of geroprotectors for Osteoporosis and Osteoarthritis, we challenge the notion that extension of lifespan correlates with extension of healthspan in all tissues and we highlight the need for more thorough studies to test the effects of geroprotectors on skeletal health in ageing organisms.

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“…Recent progresses in the field of aging research led to the development of a new class of drugs—geroprotectors, with the ability to target fundamental mechanisms of aging common to multiple age-related diseases, such as response to oxidative damage, inflammation, hypermethylation, cellular senescence, and autophagy [ 18 ]. Moskalev et al (2015) established the first public database of geroprotectors ( http://geroprotectors.org ) that indexes the most relevant experiments involving over 200 well-established geroprotectors or possible candidates that could extend the healthy lifespan and repair or reduce aging-related damage in model organisms [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Procaine–The Controversial Geroprotector Candidate: New Insights Regarding Its Molecular and Cellular Effects

Grădinaru

Ungurianu

Margină

et al. 2021

Oxidative Medicine and Cellular Longevity

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Since its discovery in 1905 and its employment in everyday medical practice as a local anesthetic, to its highly controversial endorsement as an “anti-aging” molecule in the sixties and seventies, procaine is part of the history of medicine and gerontoprophylaxis. Procaine can be considered a “veteran” drug due to its long-time use in clinical practice, but is also a molecule which continues to incite interest, revealing new biological and pharmacological effects within novel experimental approaches. Therefore, this review is aimed at exploring and systematizing recent data on the biochemical, cellular, and molecular mechanisms involved in the antioxidant and potential geroprotective effects of procaine, focusing on the following aspects: (1) the research state-of-the-art, through an objective examination of scientific literature within the last 30 years, describing the positive, as well as the negative reports; (2) the experimental data supporting the beneficial effects of procaine in preventing or alleviating age-related pathology; and (3) the multifactorial pathways procaine impacts oxidative stress, inflammation, atherogenesis, cerebral age-related pathology, DNA damage, and methylation. According to reviewed data, procaine displayed antioxidant and cytoprotective actions in experimental models of myocardial ischemia/reperfusion injury, lipoprotein oxidation, endothelial-dependent vasorelaxation, inflammation, sepsis, intoxication, ionizing irradiation, cancer, and neurodegeneration. This analysis painted a complex pharmacological profile of procaine: a molecule that has not yet fully expressed its therapeutic potential in the treatment and prevention of aging-associated diseases. The numerous recent reports found demonstrate the rising interest in researching the multiple actions of procaine regulating key processes involved in cellular senescence. Its beneficial effects on cell/tissue functions and metabolism could designate procaine as a valuable candidate for the well-established Geroprotectors database.

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The use of geroprotectors to prevent multimorbidity: Opportunities and challenges

Cited by 11 publications

References 132 publications

Zoledronate Extends Health Span and Survival via the Mevalonate Pathway in a FOXO-dependent Manner

Zoledronate Extends Health Span and Survival via the Mevalonate Pathway in a FOXO-dependent Manner

Geroprotectors and Skeletal Health: Beyond the Headlines

Procaine–The Controversial Geroprotector Candidate: New Insights Regarding Its Molecular and Cellular Effects

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