Can statin preventative treatment inform geroscience‐guided therapeutics? DOI Creative Commons
Giovanni Guaraldi, Kristine M. Erlandson, Jovana Milić

et al.

Aging Cell, Journal Year: 2023, Volume and Issue: 22(12)

Published: Oct. 13, 2023

Potential senotherapeutic effect of statins may lead to prevention and reduction frailty. People with HIV (PWH) develop cardiovascular disease (CVD) at a significantly younger age than the general population, in context multimorbid burden that is consistent an accelerated aging phenotype (Grinspoon et al., 2023). The Randomized Trial Prevent Vascular Events (REPRIEVE) study took center stage 2023 International AIDS Society (IAS) meeting Brisbane, Australia, sharing findings treatment pitavastatin reduced risk major adverse events (MACE) compared placebo PWH without pre-existing CVD Among 7769 persons (median 50 years) low-to-moderate atherosclerotic CVD, dose 4 mg daily was associated 35% lower MACE 21% and/or death over median follow-up 5.1 years on first among different subgroups, particularly ART duration >10 years, nadir CD4 cell count <200 cell/μL, current >500 cell/μL REPRIEVE builds data from previous notable primary-prevention involving statins, is, rosuvastatin landmark JUPITER (Ridker 2008), which evaluated 17,802 healthy 66 adults infection or dyslipidemia, but elevated high-sensitivity C-reactive protein (hs-CRP), inflammatory biomarker predicts vascular events. Over 1.9 there significant hs-CRP levels. Although levels have not yet been reported study, prior studies indicate biomarkers such as hs-CRP, IL-6 remain despite effective decline response statin therapy (Funderburg 2014). These trial results support growing appreciation for pleiotropic role beyond plasma low-density lipoprotein (LDL) Statins also prevent plaque formation cholesterol crystals directly activate NLRP3 inflammasome, key mediator inflammation (Koushki 2021) potentially neurocognitive (Ising 2019). Furthermore, given lipophilic are widely distributed across tissues, whereas hydrophilic appear be liver specific, carefully designed mechanistic differentiate function needed 2021). studies, considered together (pitavastatin JUPITER) inform geroprotective strategies—because tends comorbid condition (accelerated/accentuated by infection) advancing driven finite set common aging-related pathways, example, hallmarks (Burch 2014; López-Otín 2013; Toribio 2017; 2018). Whether observed LDL within antecedent molecular drivers will exciting next chapter these investigations. One attractive hallmark targeted senescence. Indeed, we propose agent, targeting senescence, either senolytics (promote clearance senescent cells) senomorphics (block proliferation senescence-associated secretory phenotype, SASP) (Coppé 2008; Matsubayashi Because cellular senescence underlies many age-related conditions, senotherapy represents promising approach mitigating conditions (e.g., metabolic disease, frailty, dementia). via inflammation, secondary lipid lowering, possibly through direct impact aging. several population suggest influence For improve endothelial alteration epigenetic pathways (Liuzzo & Pedicino, 2023) telomere attrition (Nose Interestingly, American College Cardiology has recently suggested consider geroscience therapeutic strategies older adult (Forman Notably, however, linked effects, including increased dysfunction (Abbasi 2021; Bai 2023; Centers Disease Control Pre- vention, n.d.; Mansi Sattar 2010), albeit only minimally increasing glucose study. other differ tissue effects. following infarct mitochondrial (Bland 2022). While myositis myopathy side effects outcomes tend rare. Nevertheless, their presence raises questions regarding holistic health benefit-to-burden, underscores gap our understanding mechanism action statins. HIV, recent clinical differences based biological sex statin-mediated protection loss muscle mass, strength, physical (Cárdenas Notably trial, related symptoms were marginally (2.3% vs. 1.4% arm) while no 2008). Collectively, benefits reducing cardiometabolic, biomarkers, SASP outweigh slight myopathy-related symptoms. This especially linkage between functional (Cesari 2004) frailty (Ferrucci Fabbri, Frailty, characterized critical exhaustion reserve resilience provide opportunity measure process (Afilalo Forman Frailty construct composite vulnerability stressors net result competing forces, some acting gero-protectors others gero-inducers. Ultimately, imbalance homeostatic reserves against stressors, expose individual higher negative outcomes, falls, disability, comorbidities, cognitive impairment, (Rockwood Mitnitski, 2007). Developing function-promoting interventions delay onset both healthspan lifespan critically relevant (Montano experience earlier greater prevalence people HIV-1 RNA (Desquilbet With initiation more less toxic antiretroviral therapy, demonstrated decrease aged 3-fold increase those 75 Modena Metabolic clinic, suggesting potential this specific contemporary (Guaraldi Importantly, consistently important factor multiple cohorts (Kelly 2019; Kuniholm decreasing added numerous “hallmarks”, ultimately slowing progression geriatric syndromes A substudy (PREPARE NCT04221295) collected objective measures function, area, density, subset participants (Umbleja 2020). relatively young cohort low baseline may; limit ability detect changes typically ascertained individuals 65 Finally, light findings, anticipate guidelines soon reflect PWH, dramatic change prescription rates (Jaschinski n.d.). area roll-out, end 2030 about 70% old 78% (Smit 2015). However, estimations might generalizable all geographical areas. REPRIEVE, authors noted CV factors had high income countries BMI, smoking, family history CVD) As risks expected changing epidemic obesity middle-income countries, weight modern comparison regimens, cardioprotective could even coming years. often early use conditions. represent breakthrough medicine, well broader field geroscience-guided therapeutics Giovanni Guaraldi Monty A. Montano conceptualized manuscript. Guaraldi, Kristine M. Erlandson, Jovana Milic, Alan L. Landay, wrote revised did supervision final version All contributed discussion would like thank Claudia Alonso Melissa Mendez help designing graphical abstract. received funding produce GG research grants speaker honoraria Gilead, ViiV, MERCK, Jansen. attended advisory boards ViiV MERCK. KME grant Gilead participated Merck. payments University Colorado. JM ViiV. AL receives Abbott Gilead. MM Editor Chief Aging Cell (John Wiley Sons). N/A

Language: Английский

The Quest for Eternal Youth: Hallmarks of Aging and Rejuvenating Therapeutic Strategies DOI Creative Commons
Vharoon Sharma Nunkoo,

Alexander Cristian,

Anamaria Jurcău

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(11), P. 2540 - 2540

Published: Nov. 7, 2024

The impressive achievements made in the last century extending lifespan have led to a significant growth rate of elderly individuals populations across world and an exponential increase incidence age-related conditions such as cardiovascular diseases, diabetes mellitus type 2, neurodegenerative diseases. To date, geroscientists identified 12 hallmarks aging (genomic instability, telomere attrition, epigenetic alterations, loss proteostasis, impaired macroautophagy, mitochondrial dysfunction, nutrient sensing, cellular senescence, stem cell exhaustion, defective intercellular communication, chronic inflammation, gut dysbiosis), intricately linked among each other, which can be targeted with senolytic or senomorphic drugs, well more aggressive approaches cell-based therapies. side effects seriously limit use these drugs. However, since rejuvenation is dream mankind, future research expected improve tolerability available drugs highlight novel strategies. In meantime, medical community, healthcare providers, society should decide when start treatments how tailor them individually.

Language: Английский

Citations

3
Pitavastatin is Well-Tolerated with no Detrimental Effects on Physical Function DOI
Kristine M. Erlandson, Triin Umbleja, Heather J. Ribaudo

et al.

Clinical Infectious Diseases, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 16, 2024

Abstract Background Little is known about the potential benefits or harms of statins on physical function among people with human immunodeficiency virus (PWH). Methods REPRIEVE was a double-blind randomized controlled trial evaluating pitavastatin for primary prevention major adverse cardiovascular events in PWH. Time to complete 10 chair rises, 4-m gait speed, grip strength, and modified short performance test were assessed annually up 5 years ancillary study PREPARE analyzed using linear mixed models. Findings Of 602 PWH, 52% 48% placebo. Median age 51 years; 18% female at birth; 2% transgender; 40% Black, Hispanic. follow-up 4.7 (4.3–5.0) years. Muscle symptoms (grade ≥3 treatment-limiting) occurred 5% both groups. There no evidence decline rise rate either treatment group difference compared placebo (estimated −0.10 [95% confidence interval, −.30 0.10] rises/min/year; P = .31). Small declines over time observed other tests groups, apparent differences between Interpretation We minimal middle-aged PWH This finding, combined low prevalence myalgias, supports long-term safety statin therapy function, when used

Language: Английский

Citations

1
Can statin preventative treatment inform geroscience‐guided therapeutics? DOI Creative Commons
Giovanni Guaraldi, Kristine M. Erlandson, Jovana Milić

et al.

Aging Cell, Journal Year: 2023, Volume and Issue: 22(12)

Published: Oct. 13, 2023

Potential senotherapeutic effect of statins may lead to prevention and reduction frailty. People with HIV (PWH) develop cardiovascular disease (CVD) at a significantly younger age than the general population, in context multimorbid burden that is consistent an accelerated aging phenotype (Grinspoon et al., 2023). The Randomized Trial Prevent Vascular Events (REPRIEVE) study took center stage 2023 International AIDS Society (IAS) meeting Brisbane, Australia, sharing findings treatment pitavastatin reduced risk major adverse events (MACE) compared placebo PWH without pre-existing CVD Among 7769 persons (median 50 years) low-to-moderate atherosclerotic CVD, dose 4 mg daily was associated 35% lower MACE 21% and/or death over median follow-up 5.1 years on first among different subgroups, particularly ART duration >10 years, nadir CD4 cell count <200 cell/μL, current >500 cell/μL REPRIEVE builds data from previous notable primary-prevention involving statins, is, rosuvastatin landmark JUPITER (Ridker 2008), which evaluated 17,802 healthy 66 adults infection or dyslipidemia, but elevated high-sensitivity C-reactive protein (hs-CRP), inflammatory biomarker predicts vascular events. Over 1.9 there significant hs-CRP levels. Although levels have not yet been reported study, prior studies indicate biomarkers such as hs-CRP, IL-6 remain despite effective decline response statin therapy (Funderburg 2014). These trial results support growing appreciation for pleiotropic role beyond plasma low-density lipoprotein (LDL) Statins also prevent plaque formation cholesterol crystals directly activate NLRP3 inflammasome, key mediator inflammation (Koushki 2021) potentially neurocognitive (Ising 2019). Furthermore, given lipophilic are widely distributed across tissues, whereas hydrophilic appear be liver specific, carefully designed mechanistic differentiate function needed 2021). studies, considered together (pitavastatin JUPITER) inform geroprotective strategies—because tends comorbid condition (accelerated/accentuated by infection) advancing driven finite set common aging-related pathways, example, hallmarks (Burch 2014; López-Otín 2013; Toribio 2017; 2018). Whether observed LDL within antecedent molecular drivers will exciting next chapter these investigations. One attractive hallmark targeted senescence. Indeed, we propose agent, targeting senescence, either senolytics (promote clearance senescent cells) senomorphics (block proliferation senescence-associated secretory phenotype, SASP) (Coppé 2008; Matsubayashi Because cellular senescence underlies many age-related conditions, senotherapy represents promising approach mitigating conditions (e.g., metabolic disease, frailty, dementia). via inflammation, secondary lipid lowering, possibly through direct impact aging. several population suggest influence For improve endothelial alteration epigenetic pathways (Liuzzo & Pedicino, 2023) telomere attrition (Nose Interestingly, American College Cardiology has recently suggested consider geroscience therapeutic strategies older adult (Forman Notably, however, linked effects, including increased dysfunction (Abbasi 2021; Bai 2023; Centers Disease Control Pre- vention, n.d.; Mansi Sattar 2010), albeit only minimally increasing glucose study. other differ tissue effects. following infarct mitochondrial (Bland 2022). While myositis myopathy side effects outcomes tend rare. Nevertheless, their presence raises questions regarding holistic health benefit-to-burden, underscores gap our understanding mechanism action statins. HIV, recent clinical differences based biological sex statin-mediated protection loss muscle mass, strength, physical (Cárdenas Notably trial, related symptoms were marginally (2.3% vs. 1.4% arm) while no 2008). Collectively, benefits reducing cardiometabolic, biomarkers, SASP outweigh slight myopathy-related symptoms. This especially linkage between functional (Cesari 2004) frailty (Ferrucci Fabbri, Frailty, characterized critical exhaustion reserve resilience provide opportunity measure process (Afilalo Forman Frailty construct composite vulnerability stressors net result competing forces, some acting gero-protectors others gero-inducers. Ultimately, imbalance homeostatic reserves against stressors, expose individual higher negative outcomes, falls, disability, comorbidities, cognitive impairment, (Rockwood Mitnitski, 2007). Developing function-promoting interventions delay onset both healthspan lifespan critically relevant (Montano experience earlier greater prevalence people HIV-1 RNA (Desquilbet With initiation more less toxic antiretroviral therapy, demonstrated decrease aged 3-fold increase those 75 Modena Metabolic clinic, suggesting potential this specific contemporary (Guaraldi Importantly, consistently important factor multiple cohorts (Kelly 2019; Kuniholm decreasing added numerous “hallmarks”, ultimately slowing progression geriatric syndromes A substudy (PREPARE NCT04221295) collected objective measures function, area, density, subset participants (Umbleja 2020). relatively young cohort low baseline may; limit ability detect changes typically ascertained individuals 65 Finally, light findings, anticipate guidelines soon reflect PWH, dramatic change prescription rates (Jaschinski n.d.). area roll-out, end 2030 about 70% old 78% (Smit 2015). However, estimations might generalizable all geographical areas. REPRIEVE, authors noted CV factors had high income countries BMI, smoking, family history CVD) As risks expected changing epidemic obesity middle-income countries, weight modern comparison regimens, cardioprotective could even coming years. often early use conditions. represent breakthrough medicine, well broader field geroscience-guided therapeutics Giovanni Guaraldi Monty A. Montano conceptualized manuscript. Guaraldi, Kristine M. Erlandson, Jovana Milic, Alan L. Landay, wrote revised did supervision final version All contributed discussion would like thank Claudia Alonso Melissa Mendez help designing graphical abstract. received funding produce GG research grants speaker honoraria Gilead, ViiV, MERCK, Jansen. attended advisory boards ViiV MERCK. KME grant Gilead participated Merck. payments University Colorado. JM ViiV. AL receives Abbott Gilead. MM Editor Chief Aging Cell (John Wiley Sons). N/A

Language: Английский

Citations

3