Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD): A Pilot Clinical Trial

Gonzales, Mitzi M.; Garbarino, Valentina R.; Zilli, E. Marques; Petersen, Ronald C.; Kirkland, James L.; Tchkonia, Tamar; Musi, Nicolas; Seshadri, Sudha; Craft, Suzanne; Orr, Miranda E.

doi:10.14283/jpad.2021.62

Cited by 88 publications

(96 citation statements)

References 62 publications

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“…Given that microglia become senescent and dysfunctional after clearing these possibly senescent, NFT-bearing neurons ( 105 ), therapeutic strategies to help remove senescent cells from the brain may alleviate senescent cell burden, inflammation, and disease propagation ( 90 , 98 ). Clinical trials are currently under way to test this approach ( 110 , 111 ).…”

Section: Biological Aging Hallmarks Of Cognitive Decline and Adrdmentioning

confidence: 99%

Biological aging processes underlying cognitive decline and neurodegenerative disease

Gonzales

Garbarino

Pollet

et al. 2022

Journal of Clinical Investigation

142

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Alzheimer’s disease and related dementias (ADRD) are among the top contributors to disability and mortality in later life. As with many chronic conditions, aging is the single most influential factor in the development of ADRD. Even among older adults who remain free of dementia throughout their lives, cognitive decline and neurodegenerative changes are appreciable with advancing age, suggesting shared pathophysiological mechanisms. In this Review, we provide an overview of changes in cognition, brain morphology, and neuropathological protein accumulation across the lifespan in humans, with complementary and mechanistic evidence from animal models. Next, we highlight selected aging processes that are differentially regulated in neurodegenerative disease, including aberrant autophagy, mitochondrial dysfunction, cellular senescence, epigenetic changes, cerebrovascular dysfunction, inflammation, and lipid dysregulation. We summarize research across clinical and translational studies to link biological aging processes to underlying ADRD pathogenesis. Targeting fundamental processes underlying biological aging may represent a yet relatively unexplored avenue to attenuate both age-related cognitive decline and ADRD. Collaboration across the fields of geroscience and neuroscience, coupled with the development of new translational animal models that more closely align with human disease processes, is necessary to advance novel therapeutic discovery in this realm.

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Section: Biological Aging Hallmarks Of Cognitive Decline and Adrdmentioning

confidence: 99%

Biological aging processes underlying cognitive decline and neurodegenerative disease

Gonzales

Garbarino

Pollet

et al. 2022

Journal of Clinical Investigation

142

View full text Add to dashboard Cite

show abstract

“…Though each of these biological processes has been linked to neurodegeneration and cognitive decline, a causal role for cellular senescence in neurodegenerative disease has yet to be established. Still, many contend that removal of senescent cells within the CNS may be neuroprotective in older adults, particularly in the context of AD and PD ( 23 , 174 ).…”

Section: Inflammation and The Aging Brainmentioning

confidence: 99%

Connecting aging biology and inflammation in the omics era

Walker¹,

Basisty²,

Wilson³

et al. 2022

Journal of Clinical Investigation

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Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood and solid tissues, termed inflammaging. Inflammaging has been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function. The search for mechanisms that underlie inflammaging focused initially on the hallmarks of aging, but it is rapidly expanding in multiple directions. Here, we discuss the threads connecting cellular senescence and mitochondrial dysfunction to impaired mitophagy and DNA damage, which may act as a hub for inflammaging. We explore the emerging multi-omics efforts that aspire to define the complexity of inflammaging — and identify molecular signatures and novel targets for interventions aimed at counteracting excessive inflammation and its deleterious consequences while preserving the physiological immune response. Finally, we review the emerging evidence that inflammation is involved in brain aging and neurodegenerative diseases. Our goal is to broaden the research agenda for inflammaging with an eye on new therapeutic opportunities.

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“…Quercetin is the most prominent and significant dietary antioxidant effective on health as it protects against severe diseases like lung cancer, cardiovascular disease, osteoporosis, and others [ 145 ]. There are ongoing clinical trials for estimating its accurate effect on AD [ 146 ].…”

Section: Role Of Antioxidants In Alzheimer’s Diseasementioning

confidence: 99%

Antioxidants in Alzheimer’s Disease: Current Therapeutic Significance and Future Prospects

Pritam

Deka

Bhardwaj

et al. 2022

Biology

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Alzheimer’s disease (AD) rate is accelerating with the increasing aging of the world’s population. The World Health Organization (WHO) stated AD as a global health priority. According to the WHO report, around 82 million people in 2030 and 152 million in 2050 will develop dementia (AD contributes 60% to 70% of cases), considering the current scenario. AD is the most common neurodegenerative disease, intensifying impairments in cognition, behavior, and memory. Histopathological AD variations include extracellular senile plaques’ formation, tangling of intracellular neurofibrils, and synaptic and neuronal loss in the brain. Multiple evidence directly indicates that oxidative stress participates in an early phase of AD before cytopathology. Moreover, oxidative stress is induced by almost all misfolded protein lumps like α-synuclein, amyloid-β, and others. Oxidative stress plays a crucial role in activating and causing various cell signaling pathways that result in lesion formations of toxic substances, which foster the development of the disease. Antioxidants are widely preferred to combat oxidative stress, and those derived from natural sources, which are often incorporated into dietary habits, can play an important role in delaying the onset as well as reducing the progression of AD. However, this approach has not been extensively explored yet. Moreover, there has been growing evidence that a combination of antioxidants in conjugation with a nutrient-rich diet might be more effective in tackling AD pathogenesis. Thus, considering the above-stated fact, this comprehensive review aims to elaborate the basics of AD and antioxidants, including the vitality of antioxidants in AD. Moreover, this review may help researchers to develop effectively and potentially improved antioxidant therapeutic strategies for this disease as it also deals with the clinical trials in the stated field.

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Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD): A Pilot Clinical Trial

Cited by 88 publications

References 62 publications

Biological aging processes underlying cognitive decline and neurodegenerative disease

Biological aging processes underlying cognitive decline and neurodegenerative disease

Connecting aging biology and inflammation in the omics era

Antioxidants in Alzheimer’s Disease: Current Therapeutic Significance and Future Prospects

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