Polyphenols and Diets as Current and Potential Nutrition Senotherapeutics in Alzheimer’s Disease: Findings from Clinical Trials

Abstract

Cellular senescence, a hallmark of aging, plays an important role in age-related conditions among older adults. Targeting senescent cells and its phenotype may provide a promising strategy to delay the onset or progression of Alzheimer’s disease (AD). In this review article, we investigated efficacy and safety of nutrition senotherapy in AD, with a focus on the role of polyphenols as current and potential nutrition senotherapeutic agents, as well as relevant dietary patterns. Promising results with neuroprotective effects of senotherapeutic agents such as quercetin, resveratrol, Epigallocatechin-gallate, curcumin and fisetin were reported from preclinical studies. However, in-human trials remain limited, and findings were inconclusive. In future, nutrition senotherapeutic agents should be studied both individually and within dietary patterns, through the perspective of cellular senescence and AD. Further studies are warranted to investigate bioavailability, dosing regimen, long term effects of nutrition senotherapy and provide better understanding of the underlying mechanisms. Collaboration between researchers needs to be established, and methodological limitations of current studies should be addressed.

Keywords

Alzheimer’s disease cellular senescence cognition mild cognitive impairment nutrition senotherapeutics senolytic agent

INTRODUCTION

With increased life expectancy, the older population has been growing rapidly worldwide. Among aging-related diseases, dementia affected over 55 million people globally in 2019 [1 –3], and this number is predicted to triple by the year of 2050 [3 –5]. Dementia places a significant financial and social burden on patients, carers and health care systems [6], with annual global costs estimated to reach over $2 trillion by 2030 [4, 5].

Alzheimer’s disease (AD), a neurodegenerative disorder that primarily affects older adults, is the most common type of dementia [7, 8]. The hallmarks of neuropathologic changes are neuritic plaques associated with neuronal injury, extracellular deposition of amyloid-β (Aβ) peptides, and neurofibrillary degeneration such as neurofibrillary tangles [9, 10]. Non-modifiable risk factors for AD include aging and carrying the epsilon 4 allele of the apolipoprotein E gene (APOEɛ4). Aging, characterized by a progressive loss of physiological integrity causing impaired function [11, 12], is the most important risk factor of AD, and the incidence of AD increases exponentially after the age of 65 years [1 , 14].

AD was first and still popularly explained by the Amyloid Cascade Hypothesis, which substantially impacted research into AD in recent decades [15]. The monoclonal antibodies, aducanumab, lecanemab, and donanemab showed moderately less cognitive decline in early AD clinical trials [16 –18]. Although recognizing there is a correlation between Aβ and AD pathophysiology [19], consistent concerns have been conveyed by many researchers that Aβ alone is not sufficient to cause AD: it is possible for individuals to have Aβ deposits without AD [20, 21], and AD may persist even after amyloid plaques were removed from the brain [22, 23], according to findings from several observational and experimental studies [15, 24]. Furthermore, other high profile antibodies such as solanezumab and bapineuzumab did not show cognitive benefit and led to adverse effects [25], despite lowered Aβ levels in cerebrospinal fluid (CSF) [26]. A highly complicated etiology of AD is suggested; and a simple cause-effect relationship or straightforward linear pathway mapping disease progression from Aβ to AD is inadequate [15]. Other important factors may contribute to AD onset progression; multiple avenues should be considered in the prevention and treatment of AD [19, 24].

Cellular senescence, a hallmark of aging, plays an important role in age-related conditions among older adults [27, 28]. Senescent cells resist apoptosis through senescent cell anti-apoptotic pathways [29]; insufficient clearance of senescent cells by the immune system [30, 31] especially with age-related impairment [32], leads to increased senescent cell burden [33, 34]. Senescent cells secrete pro-inflammatory cytokines, chemokines, proteases [33, 34], which jointly form the senescence-associated secretory phenotype (SASP), promoting a pro-inflammatory environment [32], resulting in tissue dysfunction [35] and metabolic dysregulation, leading to age-related disorders such as cardiovascular disease and neurodegenerative diseases [27 , 36]. Moreover, expressions of pathways involved in both cellular senescence and AD overlap [37], such as common biomarkers including tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interferon gamma (IFN-γ), suggesting that senescent cells may accelerate neurodegeneration and neuroinflammation through release of SASP factors [37].

Cellular senescence in the brain has attracted increasing research efforts in recent years. On one hand, senescent cell burden in the brain has been reported to be associated with formation of neurofibrillary tangles and tau-protein accumulation, both closely tied to AD pathology [38 –40]. Both in vitro and in vivo evidence revealed that human and mouse astrocytes could become senescent in response to exposure to multiple stress including Aβ_1–42 [41]. Cellular senescence has also been reported in endothelial cells in the dorsolateral prefrontal cortex of AD brains, which are associated with vascular dysfunction and tau pathologies [42]. Furthermore, both aging neurons and glial cells display a wealth of characteristic of cellular senescence, such as telomere erosion, lysosomal dysfunction, chromatin structure alteration and SASP [43]. The accumulation of senescent glial cells has been linked causally with deterioration of cognitive health, while clearance of these cells preserved cognition in an animal study [40]. It is worth noting that growing evidence indicates that post-mitotic neurons are capable of becoming senescent and DNA damage that accumulates in aging neurons may be an important driving factor of senescence, contributing to both brain aging and possibly AD pathogenesis [42, 44]. On the other hand, AD-related pathology may slow down clearance of senescent cells by the immune system, and thus further accelerating senescent cell burden, potentially driving a self-reinforcing circle, and escalating progression of cognitive decline and AD [45].

Targeting senescent cells and its phenotype may provide a promising therapeutic strategy for prevention and management of AD [12 , 46]. In recent years, research efforts are increasing to identify senotherapeutic agents [33], namely senolytics which selectively clear senescent cells and senomorphics which are SASP inhibitors [31 , 47–52] (see Table 1 for definitions and examples). To date, several recognized senotherapeutic agents, including natural nutritional compounds such as quercetin and resveratrol [46], have shown promising results in animal models of AD, and are in human clinical trials [46, 53]. Epidemiological studies suggested that dietary intakes of flavonoids may be associated with slower decline in global cognition and multiple cognitive domains in older age [54]. Polyphenols, with strong antioxidant and cytoprotective effects, which demonstrated therapeutic potential in AD by attenuating senescent cell accumulation and immune dysfunction [55], have attracted growing research efforts especially on identification of novel senotherapeutic agents [56]. Furthermore, foods rich in polyphenols, which are potential modulators of cellular senescence have demonstrated protective effects on cognition [57]. Recent studies reported healthy dietary patterns such as the Mediterranean diet and the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diets, which are plant-based, rich in poly- and mono-unsaturated fatty acids with lower consumption of processed foods, are promising strategies to slow, postpone or prevent aged related cognitive decline and AD [58]. Those dietary patterns were reported to have anti-senescent effects, not only due to many serotherapeutic agents such as quercetin and resveratrol which are readily available in natural foods, but also from the interplay and synergies between nutrients within a diet [58, 59].

Table 1

Definitions and examples of current/potential senolytics, senomorphics and senotherapeutics

Terminology	Definition	Examples
Senolytics/Senolytic agents [46]	Small molecules that can selectively kill senescent cells	Curcumin [99] Fisetin [134] Quercetin [37, 61]
Senomorphics/Senomorphic agents [33, 34]	Small molecules that can work as SASP inhibitors, by controlling the regulatory network of the SASP, or by targeting an SASP component. The SASP includes a variety of cytokines, chemokines, proteases, growth factors, bioactive lipids, micro-RNAs, cell-free mitochondrial DNA, and microsomes and exosomes [31 , 34].	Anthocyanin [52] Apigenin [50] EGCG [94] Glucosamine [48] Kaempferol [50] Metformin [47] Resveratrol [56, 100]
Senotherapeutics/Senotherapeutic agents [33, 34]	Agents that target both of the processes of senolytics which selectively target senescent cells and senomorphics which act as SASP inhibitors [70].	Examples as above
Nutrition senotherapy	Nutrition interventions that focus on targeting and modifying cellular senescence and related phenotype (SASP), using either nutrition senotherapeutic agents alone, or diets rich in nutrition senotherapeutic agents.	Polyphenols [32, 56] Mediterranean diet [59]

EGCG, epigallocatechin gallate; SASP, senescence-associated secretory phenotype.

In this narrative review, our aim was to investigate whether recent evidence supports the efficacy and safety of nutritional senotherapy in AD, with a focus on the role of polyphenols as senotherapeutic agents and dietary patterns in existing clinical trials. We discuss the treatment potential of using nutrition senotherapy to delay the onset or progression of AD, summarize what lessons have been learnt from pre-clinical and clinical trials so far, and provide insights to future clinical trials with reference to up-to-date scientific literature.

RESEARCH METHODS

This review focuses on existing clinical trials on nutrition senotherapy in AD from clinicaltrials.gov and trialsearch.who.int, the International Clinical Trial Registry Platform. We also searched Medline and Cochrane, and identified published articles related to registered clinical trials or interventional studies in past five years. Search terms were ‘serotherapeutic’ or ‘senolytic’ or ‘senomorphic’ and assorted combinations of the following terms: ‘Alzheimer*’, ‘Alzheimer’s disease’, ‘dementia’, ‘cognitive impairment’, and/or ‘cognitive decline’. We searched for ‘diet’ or ‘nutrition’ or ‘polyphenol’ to prevent exclusion of relevant studies on potential nutrition senotherapeutics, and for systematic reviews and meta-analyses of interventional studies. Titles and abstracts were screened after initial search to identify eligible studies; irrelevant studies removed. In-human clinical trials on nutrition senotherapeutic agents and diets were included. We excluded studies not written in English, targeting younger populations, not including AD, Alzheimer* or cellular senescence, or not providing full text.

RESULTS

Results for individual senotherapeutic agents and dietary patterns are presented as below.

Quercetin

Quercetin is a flavanol found in a variety of fruits and vegetables such as onions, apples, berries and broccoli [60]. Quercetin was reported to ablate senescent endothelial cells and bone marrow-derived mesenchymal stem cells in mice models, by targeting the BCL-2 and PI3K/Akt pathways [61]. A systematic review published in 2020, identified 14 pre-clinical studies that reported neuroprotective effects of quercetin supplementation (dosage varied from 5 mg/kg/day to 2000 mg/kg/day) on different AD animal models [62]. A subsequent meta-analysis by forest plot to examine the effects of quercetin (20–30 mg/kg, treatment duration from 2 weeks to 3 months) in mice AD models, reported significant improvement in cognitive function among treatment groups, measured by the Morris water maze [62]. Recent studies reported a remarkable improvement in the cognitive performance [63], decreased pro-inflammatory cytokines and reactive oxygen species [64], enhanced sirtuin1 expression, suppressed nuclear factor-kappa B (NF-κB) activation [65], and significantly reduced Aβ immune reactivity in the quercetin treated groups [63]. The neuroprotective mechanisms of quercetin involve inhibition of Aβ aggregation [66], tau phosphorylation [67], amelioration of mitochondrial dysfunction [68], and anti-oxidative and anti-inflammatory activities in animal models [62, 69].

Quercetin, when combined with dasatinib (an anti-cancer agent identified as senolytic [31]), was reported to target a wider range of senescent cell types compared to either agent alone [70]. The combination of quercetin and dasatinib has shown senolytic activities such as efficient acceleration of senescent cells apoptosis and reduction of age-related disease in animal models [61, 71], resulting in positive effects on learning and memory which persisted at least 5 weeks after the intervention [72]. Exploratory studies that investigated underlying mechanisms reported that this senolytic mixture effectively decreased neuroinflammation, partly reversed brain atrophy and significantly improved AD pathology of tau or Aβ protein accumulation [27 , 74].

Overall, five human clinical trials were identified from clinicaltrials.gov (Supplementary Table 1). One completed with results (NCT04063124), one completed (NCT01716637) with no results posted, two recruiting (NCT04685590, NCT05422885), and one enrolling by invitation (NCT04785300). Among the registered trials, the largest human trial of senolytic therapy for AD (NCT 04685590) is SToMP-AD, a current Phase II multisite, randomized, double-blind placebo-controlled trial that will investigate safety and efficacy of senolytic therapy in AD over a 12-week treatment period, estimated to enroll 48 participants and complete final data collection by 2027 [37].

An open-label, proof-of-concept, phase I clinical trial (NCT04063124) was conducted among five early-stage AD patients with intermittent oral administration of dasatinib (100 mg) and quercetin (1000 mg) (see Table 2 for details). This 12-week trial reported a statistically significant decrease in Hopkins Verbal Learning Test-Revised Immediate Recall, while no significant changes in other cognition and neuropsychiatric tests [75]. Among AD related biomarkers, an elevation was detected in CSF glial fibrillary acidic protein (GFAP), a marker of astrocyte activity, levels post-treatment; but there were no significant changes in tau, Aβ and NFL in either blood or CSF. Among biomarkers of cellular senescence and SASP, plasma levels of IL-17E, IL-21, IL-23, IL-17A/F, IL-17D, IL-10, vascular endothelial growth factor, IL-31, MCP-2, macrophage inflammatory protein (MIP)-1β and MIP-1α reduced from baseline to post-treatment; CSF levels of senescence-related cytokines and chemokines decreased while IL-6 levels increased from baseline to post-treatment. Overall, the treatment was well tolerated [75].

Table 2

Characteristics of clinical trials on nutrition senotherapeutic agents included in the review

Author, year, location	Participants and setting	Nutrition senotherapeutic agent	Dosing regimen and adverse effects	Measurement of outcome	Key findings
Gonzales et al. 2023 [75] US	Study design: An open-label pilot study with single group assignment Participants:N = 5 with early AD Mean age: 76 years Female: 40%	Quercetin supplementation	Intermittent oral administration of Quercetin (1000 mg) plus dasatinib (100 mg) for 2 days on then 14 days off for 6 cycles, over 12 weeks AE no serious AE; one moderate AE, hypoglycemia, was possibly related to the intervention. Mild AEs deemed unlikely related to the study (diarrhea and emesis, urinary tract infection).	Plasma and CSF levels of quercetin and dasatinib; total tau, pTau181, pTau231, Aβ₄₀, Aβ₄₂, GFAP, senescence marker of IL-6, senescence-related cytokines and chemokines in the CSF; pTau181, Aβ₄₀, Aβ₄₂, GFAP, NFL, senescence marker of IL-6, senescence-related cytokines and chemokines in blood. Cognitive tests: Montreal Cognitive Assessment, Wechsler lV Memory Scale, Benson Figure, California Verbal Learning Test II Short Form	Cognitive results did not significantly differ from baseline to post-treatment. In CSF, dasatinib levels were detected in four participants (80%), quercetin was not detected; dasatinib and quercetin levels in blood increased in all participants. CSF levels of IL-6 and GFAP increased (p = 0.008 and p = 0.028, respectively) with trending decreases in senescence-related cytokines and chemokines, and a trend toward higher Aβ₄₂ levels (p = 0.079).
Nakamura et al. 2022 [78] Japan	Study Design: A randomized, double-blind, placebo-controlled trial Participants:N = 68 without MCI Mean age: 66 years Female: 65%	Quercetin (quercetin glycoside-containing beverage)	Continuous oral intake of 500 ml beverage per day, containing 110 mg of quercetin glycoside as isoquercitrin, over 40 weeks. AE No other adverse events were causally related to the study, apart from frequent urination due to drinking beverages.	MMSE, Cognitrax (a computerized cognitive function test) NIRS, cerebral blood flow measurement; IGF-1, Plasma Aβ₄₀, Aβ₄₂, Tau, NFL, TNF-α, interleukin-6, and interferon-gamma. Body composition and blood pressure; plasma antioxidant marker levels, lipid levels, glucose metabolism, liver function, kidney function, albumin, and total protein levels.	Reaction time significantly improved in the intervention group. The cerebral blood flow suggested that a positive trend that quercetin glycoside intake could likely suppress the decrease in cerebral blood volume, cerebral blood flow, and cerebral activity owing to stress alleviation and inhibition of the accumulation of Aβ (not statistically significant).
Nishihira et al. 2021 [77] Japan	Study Design: A randomized, double-blind, placebo-controlled trial Participants:N = 61 with MMSE > 23 Mean age: 70 years Female: 56%	Quercetin (a powder made from dried quercetin-rich onions, namely ‘Sarasara-gold’, as active test food)	Continuous oral intake of quercetin rich onion as the active test food (50 mg as aglycone equivalent per day) made from quercetin-rich onions, over 24 weeks AE not observed in this study in terms of food safety.	MMSE, CADi2 including the verbal recall test, and NPI. Body composition and blood pressure; plasma antioxidant marker levels, lipid levels, glucose metabolism, liver function, kidney function, albumin, and total protein levels.	The MMSE scores were significantly improved in the active test food group compared to the placebo group after 24 weeks. On the CADi2 for emotional function evaluation, scores of the intervention group significantly improved.
Nishimura et al. 2017 [76] Japan	Study Design: A randomized, double-blind, placebo-controlled trial Participants:N = 50 with MCI or healthy, without AD Mean age: 72 years Female: 50%	Quercetin (a powder made from dried quercetin-rich onions, namely ‘Quergold’ and ‘Sarasara-gold’, as active test food)	Continuous oral administration of the powder 10 g/day (equivalent to 60 mg Quercetin glycoside per day) made from quercetin-rich onions, over 24 weeks AE Few subjects exhibited mild symptoms (details not reported) and recovered, no AE related to the test.	MMSE, cognitive impairment rating scale (executive function, memory recall, immediate memory, and short-term memory), and NPI. Body composition and blood pressure; plasma antioxidant marker levels, lipid levels, glucose metabolism, liver function, kidney function, albumin, and total protein levels	No differences in the MMSE and cognitive impairment rating scale scores between the two groups. However, in younger subjects (aged 65 to 72 years), the MMSE scores were significantly higher in the active test food group than in the placebo food group at week 24 (p = 0.019).
Gu et al. 2021 [85] China	Study Design: A randomized, double-blind, placebo-controlled trial Participants:N = 30 with mild to moderate AD Mean age: 72 years Female: 47%	Resveratrol (supplementation in the form of trans-resveratrol)	Continuous oral intake of 500 mg trans-resveratrol once daily, over 52 weeks AE The most frequent AEs were nervous system disorders and GI disorder, however no between group differences.	MMSE, CSF Aβ₄₀, CSF Aβ₄₂ and plasma Aβ₄₂, CSF tau and phospho-tau 181, CSF MMP-9.	Changes in of Aβ₄₀ in blood/ CSF of treatment group were not significant, while control showed a significant decrease; brain volume of treatment group reduced (p = 0.011) and MMP-9 decreased in the CSF of treatment group compared with control (p = 0.033).
Zhu et al. 2018 [86] US	Study Design: A randomized, double-blind, placebo-controlled trial Participants:N = 39 with mild to moderate AD Mean age: 80 years Female: 43.4%	Resveratrol (supplementation for 5 mg daily in a liquid form)	Continuous oral intake of 15 mL of a regimen consisted of 5 g dextrose, 5 g malate, and 5 mg resveratrol, over 1 year AE The most common AE were falls, all in the control group. No AE related to study. Resveratrol is safe and well tolerated.	MMSE ADAS-cog NPI	At 12 months, change scores on MMSE, ADAS-cog and NPI all showed less deterioration in the treatment than the control group; however, none of the change scores reached statistical significance.
Turner et al. 2015 [83] Moussa et al. 2017 [84] US	Study Design: A multi-site, randomized, double-blind, placebo-controlled trial Participants:N = 119 with mild to moderate AD Mean age: 72 years Female: 57%	Resveratrol (supplementation for up to 1 g by mouth twice daily)	Continuous oral intake of resveratrol 500 mg once daily (with a dose escalation by 500-mg increments every 13 weeks, ending with 1000 mg twice daily), over 52 weeks AE The significant adverse event was weight loss. No between group differences for other AEs.	MMSE; AD biomarkers (plasma Aβ₄₀ and Aβ₄₂, CSF Aβ₄₀, Aβ₄₂, tau, and phospho-tau181); CSF markers indicative of inflammation, including FGF-2, TGF-α, Fractalkine, IFNα2, IL-10, IL-12P40, IL-12P70, IL-13, IL-15, IL-17A, IL-1RA, IL-1α, IL-9, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IP-10, MIP-1β, RANTES, TNFα, TNFβ.	Compared to control group, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine, IL-4, and FGF-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In a subset (N = 38) analysis, resveratrol treatment attenuated declines in MMSE, and CSF Aβ₄₂ levels during the 52-week trial.
Sakurai et al. 2020 [96] Japan	Study Design: A randomized, double-blind, placebo-controlled trial Participants:N = 61 without MCI/AD Mean age: 74 years Female: 64%	EGCG (3 g powder from fresh Matcha daily)	Continuous oral intake 15 of g powder containing 1.5 g Matcha new green tea powder (277 mg EGCG equivalent), with non-dairy creamer and low calories sweetener, twice a day, over 12 weeks AE not reported.	MoCA, MMSE, WMS-DR, BIS-11	No significant changes in cognitive test scores before and after the experiment, between the active and placebo groups. No significant change was seen in WMS-DR and BIS-11) between the active and placebo groups. In female subgroup, significant improvement in MoCA in intervention compared to control (p = 0.01).
Baba et al. 2020 [97] Japan	Study Design: A randomized, double-blind, placebo-controlled trial Participants:N = 47 with MMSE > 24 and self-reported cognitive decline Mean age: 58 years Female: 50%	EGCG (natural food source, green tea extract)	Continuous oral intake of green tea extract daily (216.9 mg EGCG equivalent), over 12 weeks AE not reported.	Serum changes in blood BDNF, Aβ_1–40, Aβ_1–42, APP770, and sAPPα levels; the Cognitrax testing battery (verbal memory test, visual memory test, finger-tapping test, symbol digit-coding test, continuous performance test, POET, NVRT, ST, SAT, FPCPT)	The incorrect response rate on the continuous performance pest significantly decreased after a single dose; after 12 weeks, the response time for part 4 of continuous performance test, a two-back test, was shortened. No serum changes in BDNF, Aβ_1–40, Aβ_1–42, APP770, and sAPPα.
Ringman et al. 2012 [110] US	Study Design: A randomized, double-blind, placebo-controlled trial Participants:N = 36 with mild to moderate AD Mean age: 74 years Female: 63%	Curcumin (supplementation)	Continuous oral intake of 2 grams/day, or 4 grams/day of curcumin supplementation, over 24 weeks, with an open-label extension to 48 weeks AE 4/35 (11.4%) subjects on curcumin dropped out due to GI side effects (black stools, diarrhea, or difficulty swallowing the pills)	MMSE, ADAS-cog, NPI. Levels of Aβ_1 - 40 and Aβ_1 - 42 in plasma and levels of Aβ_1 - 42, t-tau, p-tau181 and F2-isoprostanes in CSF. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured.	There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL).
Vina et al. 2022 [118] Spain	Study Design: A bicentric, randomized, double-blind, placebo-controlled trial Participants:N = 24 with prodromal AD, MMSE> =24 Mean age: 68 years Female: 33%	Isoflavones (genistein supplementation)	Continuous oral intake, daily supplementation with 120 mg of genistein, Over 12 months AE No serious AE. In the genistein group, one of the 14 patients withdrew from the trial (mild diarrhea was reported).	MMSE, Memory Alteration Test, Clock Drawing Test, TAVEC, Barcelona Test-Revised, and Rey Complex Figure Test, Aβ deposition	In intervention group, significant improvement in dichotomized direct TAVEC (p = 0.031); dichotomized delayed Centil REY copy (p = 0.002). The Aβ deposition analysis showed that intervention group did not increase their uptake in the anterior cingulate gyrus (p = 0.878), while control group did increase it (p = 0.036).
Gleason et al. 2015 [116] US	Study Design: A randomized, double-blind, placebo-controlled trial Participants:N = 59 with AD Mean age: 76 years Female: 51%	Isoflavones (supplementation)	Continuous oral intake, daily supplementation with 100 mg of soy isoflavones, over 6 months AE No subjects were discontinued due to abnormal safety.	A battery of neuropsychological measures of verbal and visuospatial memory, language, executive function, working memory and visual-motor function	Six months of treatment with soy isoflavones did not benefit cognition in older men and women with AD.
Aarsland et al. 2023 [126] Norway	Study Design: A randomized, double-blind, placebo-controlled trial Participants:N = 206 with MCI/ CMD Mean age: 69 years Female: 50%	Anthocyanins (naturally purified)	Continuous oral intake of 320 mg/day of naturally purified anthocyanins over 24 weeks AE Capsules were well tolerated with high compliance, majority AEs reported were 8 mild/moderate GI disorders and 3 serious cases of AEs (cardiac disorders), no significant difference between groups.	The Quality of Episodic Memory composite measure (0–100) and other cognitive tests from an online cognitive test battery CogTrack.	No significant group difference in cognition at 24 weeks. However, there was a significant difference in slopes during weeks 8–24 (p = 0.007): the anthocyanin group improved while the placebo group worsened.
Rosario et al. 2021 [125] Australia	Study Design: A randomized, double-blinded, placebo-controlled trial Participants:N = 31 with MCI Mean age: 76 years Female: 61%	Anthocyanins (natural food source)	Continuous oral intake of 250 ml/day of fruit juice (high dose of 201 mg anthocyanins equivalent), low dose of 47 mg anthocyanins equivalent, and control), over 8 weeks AE Not reported.	Serum IL-6, IL-1b, CRP and TNF-α.	Participants in the high anthocyanins group had a reduction in TNF-α (p = 0.002) compared to controls and the low anthocyanins group. Serum IL-6, IL-1b, CRP were not altered by any treatment.
Krikorian et al. 2020 [123] US	Study Design: A randomized, double-blinded, placebo-controlled trial Participants:N = 37 with MCI Mean age: 77 years Female: 54%	Anthocyanins (natural food source)	Continuous oral intake of whole freeze-dried blueberry fruit powder 24 g daily, equivalent to 1 cup whole fruit and contained 258 mg cyanidin 3-glucoside equivalents of parent anthocyanins, over 12 weeks AE Not reported.	Neuropsychological testing included measures of speed of processing, working memory, lexical access, verbal and non-verbal long-term memory, and symptoms of cognitive decline (trail making test, HVLT, word list learning and recall task, SPAL; paired visual stimuli test)	Intervention group improved in semantic access (p = 0.01) and visual-spatial memory (p = 0.05). Level of parent anthocyanins were 100 times greater in intervention group, and correlated with neurocognitive benefit.
Miller et al. 2018 [127] US	Study Design: A randomized, double-blinded, placebo-controlled trial Participants:N = 37 with MCI Mean age: 68 years Female: 67%	Anthocyanins (natural food source)	Continuous oral intake of freeze-dried blueberry 24 g daily, equivalent to 1 cup whole fruit and contained 461 mg anthocyanins, over 12 weeks AE Not reported.	Cognitive test battery, executive function assessed by TST, executive function and psychomotor speed assessed using TMT, long-term memory assessed using CVLT, Spatial cognition measured by the Morris Water Maze; attention measured using ANT, mood assessed by GDS.	Participants in the blueberry group showed significantly fewer repetition errors in the California Verbal Learning test (p = 0.031) and reduced switch cost on a task-switching test (p = 0.033) across study visits.
Kent et al. 2017 [124] Australia	Study Design: A randomized, placebo-controlled trial Participants:N = 49 with mild to moderate AD Mean age: 80 years Female: 50%	Anthocyanins (natural food source)	Continuous oral intake of 200 ml/day of anthocyanin-rich cherry juice (138 mg anthocyanin equivalent), over 12 weeks AE Not reported.	A battery of seven cognitive tests, including the Rey Auditory Verbal Learning Test, the self-ordered pointing task, the Boston naming test, TMT, digit span backwards task and category and letter verbal fluency. CRP and IL-6.	Improvements in verbal fluency (p = 0.014), short-term memory (p = 0.014) and long-term memory (p≤0.001) were found in the cherry juice group. Markers of inflammation (CRP and IL-6) were not altered.

AD, Alzheimer’s disease; AE, adverse events; CSF, cerebrospinal fluid; pTau, phosphorylated tau; Aβ, amyloid-beta; GFAP, glial fibrillary acidic protein; IL, interleukin; NFL, neurofilament light; MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory; CADi2, Cognitive Assessment for Dementia iPad version; NIRS, near-infrared spectroscopy; IGF, insulin-like growth factor; NFL, neurofilament light; TNF, tumor necrosis factor; ADAS-cog, Alzheimer’s Disease Assessment Scale – cognitive subscale; MMP, metalloproteinase; FGF, fibroblast growth factor; GI, gastrointestinal; SCD, subjective cognitive decline; MoCA, Montreal Cognitive Assessment; WMS-DR, Wechsler Memory Scale-Delayed Recall; BIS, Barratt Impulsiveness Scale; BDNF, brain-derived neurotrophic factor; APP, amyloid precursor protein; sAPPα, secreted form of amyloid precursor protein α; POET, perception of emotions test; NVRT, Non-Verbal Reasoning Test, ST, Stroop Test; SAT, Shifting Attention Test; FPCPT, 4-Part Continuous Performance Test; TAVEC, Complutense Verbal Learning Test, CMD, cardiometabolic disorders; CRP, C-Reactive Protein; HVLT, the Hopkins Verbal Learning Test; SPAL, Spatial Paired Associates Learning Test; TST, Task-Switching Test; TMT, Trail Making Test; CVLT, California Verbal Learning Test; ANT, Attention Network Task; GDS, Geriatric Depression Scale.

An earlier randomized controlled trial (RCT) (UMIN 000015940, from a Clinical Trials Registry hosted by the Japanese University Hospital Medical Information Network) of quercetin-rich onions reported significantly improved Mini-Mental State Examination (MMSE) scores after 24 weeks in 50 dementia-free subjects who were healthy or with MCI, aged 65 to 72 years who consumed 10 g onion powder per day (containing 60 mg quercetin glycoside equivalent daily) [76]. Later, Nishihira et al. [77] reported improvement in both cognition and emotion from a larger RCT (n = 61) with the same study design and using quercetin-rich onion powder as the active test food for the intervention group (UMIN000036276). A similar trial (UMIN000038593) with a longer duration of 40 weeks among older adults without MCI, reported no significant between-group differences in MMSE, but reaction time improved in intervention group who consumed quercetin-containing beverage (110 mg of quercetin glycoside as isoquercitrin per day) [78].

Resveratrol

Resveratrol is a polyphenol, found in highest levels in red wine and the skin of red grapes, and rich in berries, chocolate and peanuts [56]. A systematic review of 19 pre-clinical studies [79] supported neuroprotective effects of resveratrol in AD animal models, through multiple bioactivities including prohibition of Aβ production and aggregation, suppression of tau hyperphosphorylation, inhibition of inflammation, and protection of neurons from reactive oxidative stress [79]. Apart from anti-inflammatory and anti-oxidative properties of resveratrol [80], mechanistic studies reported resveratrol plays a neuroprotective role via signaling pathways such as SIRT1, activates sirtuins, a class of enzymes usually triggered by caloric restriction which has been linked to improvement in aged-related disorders and regulation of cellular senescence [79, 81]. However, results of resveratrol effects on cognitive function from in-human studies were inconsistent [82].

Currently five clinical trials of resveratrol can be found in clinicaltrials.gov (Supplementary Table 1), of which two were completed with results (NCT01504854, NCT00678431), two were completed (NCT02502253, NCT01716637) with no results posted, and one was withdrawn (NCT00743743). In the completed RCT over 52 weeks (NCT01504854) involving 119 participants with mild-to-moderate AD, the oral dosage of resveratrol supplement in the intervention group started at 500 mg/day then increased by 500 mg at 13-week intervals to a maximum of 1 gram twice a day (see Table 2 for details) [83, 84]. At the end of this trial, Aβ₄₀ in plasma and CSF had significantly less decline in the intervention group than controls [83]. Results from a secondary analysis in a subgroup of participants (N = 38, CSF Aβ₄₂ < 600 ng/ml at baseline, i.e., biomarker-confirmed AD) suggested that resveratrol attenuated declines in MMSE scores and CSF Aβ₄₂ levels, and significantly decreased CSF metalloproteinases (MMP)-9, and pro-inflammatory biomarkers in plasma (IL-12P40, IL12P70, and RANTES) [84]. Another 52-week AD trial [85] reported similar findings in changes of Aβ₄₀ in plasma and CSF, and the level of MMP-9. Both studies reported brain volume loss at the end of the intervention, possibly due to reduction of brain oedema [83, 85].

By contrast, one AD trial (NCT00678431) with a much lower dosage of resveratrol (5 g dextrose, 5 g malate, and 5 mg resveratrol per day) over a year reported no statistical significance in MMSE or Neuropsychiatric Inventory (NPI) scores when comparing the intervention and placebo groups [86]. Both low-dose and high-dose oral resveratrol used in the above cited trials were reported to be safe and well-tolerated among older adults with AD [84, 86]. Previous studies reported resveratrol was well tolerated and pharmacologically safe with an oral intake up to 5 g/day [83, 87].

Epigallocatechin-gallate (EGCG)

EGCG is a bioactive polyphenol found in green tea [88]. Supplementation of EGCG has been reported to slow the progression of AD and attenuate cognitive decline in an AD animal model [89]. EGCG can act as an SASP modulator by inhibiting the Akt/mTOR pathway, and potentially as a senolytic agent which triggers senescent cell death by regulation of the Bax/Bcl-2 pathway [90, 91]. Findings from a systematic review and meta-analysis of 17 pre-clinical studies which assessed the impact of EGCG in animal AD models, supported neuroprotective properties of EGCG, reported positive results of shorter escape latency in the Morris water maze test, improved learning or memory, and an overall decreased plasma Aβ₄₂ level and phosphorylation of tau in animal models [92]. Most reported adverse events were mild and not significantly different from the placebo group [92]. Possible mechanisms of action include anti-neuroinflammation, regulation of α-, β-, and γ- secretase activities, inhibition of Aβ deposition and secretase activity [93], suppression of acetylcholinesterase activity, and amelioration of oxidative stress [92 –94]. Dosage of EGCG varied across pre-clinical trials; more than half of the studies used 800 mg of EGCG daily which was generally well tolerated with study durations ranging from 6 weeks to 1 year [92].

Two human trials were listed on clinicaltrials.gov (NCT03978052, NCT00951834). A study planned to investigate the effects of a combination of EGCG (260–520 mg EGCG daily) and multimodal intervention (dietary consult, physical activity, cognitive training, and social engagement) for AD prevention among APOE4 carriers of AD with subjective cognitive decline as the primary outcome of interest (NCT03978052) [95]; the status of this trial is ‘unknown’ and no findings have been published (Supplementary Table 1). An earlier clinical trial of EGCG on early stage of AD (NCT00951834) provided 200 to 800 mg Sunphenon EGCG for intervention over 18 months; no results have been forthcoming, according to our knowledge (Supplementary Table 1). Furthermore, supplementation of 3 g/d of matcha green tea powder demonstrated protective effects against cognitive decline in 61 healthy elderly women in a 12-week RCT in Japan (UMIN000036331) [96]. Benefits on working memory were reported by another 12-week Japanese trial (UMIN000033813) which provided green tea extract containing EGCG equivalent 216.9 mg daily (Table 2). However, serum levels of Aβ, the secreted form of Aβ precursor protein α, and brain-derived neurotrophic factor remained unaltered [97].

Curcumin

Curcumin, a yellow substance extracted from the spice turmeric, has antioxidant, anti-inflammatory, and cholesterol-lowering properties, and has been shown to be beneficial for prevention of cellular senescence and maintenance of telomere [98, 99]. This may be a promising agent to reduce neuroinflammation and SASP activities [100]. Molecular mechanisms of curcumin were related to enhanced superoxide dismutase activity, decreased malondialdehyde and lipofuscin levels, and modulation of signaling pathways including IIS, mTOR, PKA, and FOXO [98]. According to epidemiological studies, considerably lower prevalence of AD in countries such as India has been hypothesized to result from higher curcumin consumption in long term, when compared to the US that have low curcumin intakes [98, 101]. When tested in animal models of AD, curcumin significantly modified microglial activity, inhibited acetylcholinesterase, downregulated GFAP expression, improved spatial memory, and prevented cognitive deficits [102 –104]. In addition, curcumin also reversed amyloid aggregation, suppressed tau-phosphorylation in AD mouse models [98 , 105–107], and demonstrated even stronger synergetic effects on decreasing inflammatory responses and Aβ production when used in combination with other natural compounds such as berberine [108].

Overall results from human trials of cognition have been inconsistent [109]; trials in humans with AD are scarce. A 24-week randomized, double blind, placebo-controlled study (NCT00099710) investigated tolerability and efficacy of curcumin among 30 participants with mild-to-moderate AD, and reported no between-group differences in cognition or AD-related biomarkers (such as levels of Aβ₄₀ and Aβ₄₂ in plasma and CSF, and total-tau, phospho-tau181 in CSF) [110]. This study reported that curcumin was generally well-tolerated although three subjects withdrew due to gastrointestinal symptoms (Table 2) [110]. No results have been published (see Supplementary Table 1 for details) from other registered clinical trials (NCT00164749, NCT01811381, NCT01716637, NCT01001637).

Isoflavones

In senescence-accelerated animal models, isoflavones improve central cholinergic function, enhance the learning and memory ability via reduction of the β-secretase activity to decrease Aβ deposition [111]. A meta-analysis of 16 RCTs (1,386 participants, mean age 60 years) reported that soy isoflavones may improve cognitive function [112], however results from observational studies remain mixed [113, 114], and little research has been conducted to investigate effects of isoflavones in AD specifically.

Two AD clinical trials of isoflavones were found (NCT00205179, NCT01982578). In a preliminary study of 30 participants, oral administration of 100 mg soy isoflavones supplement per day was well tolerated, but effects on cognitive tests were inconsistent [115]. After six months, the treatment group with soy isoflavones had improved in visual-spatial memory, construction, and verbal fluency; however, participants in the control group were faster in two executive function tests [115]. A clinical trial conducted later (NCT00205179) with a similar study design but larger sample (N = 59) reported that soy isoflavones did not benefit cognition among participants with AD [116]. A recent 12-month RCT (NCT01982578) that compared120 mg genistein supplementation in 24 prodromal AD patients (according to the IWG-2 criteria [117]), reported that compared to control group, participants in the intervention group had less Aβ deposition in brain, and significantly improved in memory, learning, attention and executive function [118].

Other nutritional senotherapeutics

Polyphenols, representing thousands of bioactive compounds that are found in many fruits and vegetables, may act as senolytic agents or SASP suppressors [32 , 53]. A recent systematic review and meta-analysis on the overall effect of polyphenol interventions on cognitive function among healthy older adults that included 15 high quality RCTs, failed to provide evidence regarding the protective effect on cognitive health. However, possible beneficial effects of polyphenols depend on their ingested dose and bioavailability [119]. Furthermore, the type of polyphenol supplementation used in selected studies in this meta-analysis varied (resveratrol supplementation, grape and blueberry extract, red clover extract, soy isoflavones, polyphenol-rich cocoa, ginkgo biloba, and wild berry extract) [119].

Preclinical studies showed beneficial effects with anthocyanins in AD [120]. Consistently, a systematic review of 18 RCTs that investigated effects of berry anthocyanins (a subclass of flavonoids) on cognitive performance found beneficial effects on memory in the majority of studies [121]. Food-based anthocyanin consumption improved cognition in both acute and longer term [122]. An RCT (NCT00599508) that provided blueberry supplementation comprising 24 g dried fruit powder/day (equivalent to 1 cup whole fruit), reported improved semantic access and visual-spatial memory in older adults with MCI [123]. Among participants with mild to moderate AD (mean age 80 years), 12-week intervention of 138 mg anthocyanin daily (ACTRN12614001298606, Australian New Zealand Clinical Trials Registry) from natural food source (cherry juice), reported improvements in verbal fluency, short-term memory and long-term memory, although inflammatory biomarkers of IL-6 and CRP were unchanged [124]. Similar results on inflammatory biomarkers were reported by a shorter-term trial of 8 weeks on people with MCI, except for a significant reduction in TNF-α among participants received intervention of 201 mg anthocyanin equivalent from fruit juice (see Table 2 for details) [125]. A 24-week RCT (NCT03419039) comparing 320 mg naturally purified anthocyanins per day and placebo in participants at high risk of AD (with MCI or cardiometabolic disorder) reported improved cognition in the intervention group and worse cognition in the control group [126]. Another RCT on 37 participants with MCI (NCT01888848) reported that, after a high dose of 461 mg anthocyanins from blueberries for 12 weeks, the intervention group demonstrated better long-term memory and executive function (see Table 2 for details) [127]. Similar to other nutrition senotherapeutics, multiple underlying mechanisms may include oxidative stress reduction, prevention of neuroinflammation and tau hyperphosphorylation in AD [120]. A “purple diet” RCT is underway (ACTRN12622000065796), to investigate whether a diet rich in anthocyanins with natural foods or powder, could sustainably delay or prevent cognitive decline among older adults with amnestic MCI [128].

Fisetin is a natural flavonoid, found in small amounts in strawberry, persimmon, kiwi fruit, peaches, grapes, tomatoes, onions, and cucumbers. The biological activities of fisetin, according to animal studies, involve multiple signaling pathways such as the PI3K/Akt, NF-κB, and NRF2 pathways [129, 130]. Moreover, in AD animal models, fisetin consistently attenuated cognitive decline [131], prevented neuroinflammation, inhibited Aβ accumulation and tau aggregation [132], protected against Aβ neurotoxicity. Although recognized as a promising senolytic agent and reported to result in significant reduction of cellular senescence in human adipose tissues [56 , 133–135], no AD clinical trials have been conducted using fisetin thus far, according to our knowledge. Fisetin may be a promising candidate for in-human trials and future development as a preventive or therapeutic agent for AD [136].

Existing trials of a variety of flavonoids have reported mixed results. Hippocampal-dependent list-learning performance improved after 770 mg flavanol intake daily for 12 weeks, particularly in participants with the lowest diet quality (measured by the alternative Healthy Eating Index) [137]. By contrast, another study on dark chocolate flavanols reported that healthy older adults showed no effect on cognition following eight-weeks of daily consumption of 50 g dark chocolate containing 410 mg flavanols [138]. Promising results were reported for 12 months intervention using high and moderate phenolic content extra virgin olive oil, with both associated with significant improvement in cognitive function compared to a Mediterranean diet only, independent of the presence of APOEɛ4 [139].

Dietary patterns

Overall, the most researched dietary patterns are the Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH) diet, and MIND diet. Although dietary patterns were not commonly recognized as typical senotherapeutics, many multiple senolytic and senomorphic agents such as quercetin and resveratrol are readily available in the form of nature foods among the above listed diets. Those dietary patterns are also rich in multiple polyphenols which are potentially senotherapeutic, therefore highly likely have an impact on cellular senescence and AD [59, 140]. Mediterranean diet was reported to associate with “anti-senescence effects” [59] with possible underlying mechanism via its anti-inflammatory and antioxidant properties, as well as improvement of gut microbiota [141]. A systematic review and meta-analyses confirmed that higher adherence to the Mediterranean [142], DASH, or MIND diets was associated with less cognitive decline and a lower risk of AD, while the MIND diet had the strongest association with these outcomes [143]. Buckinx et al. concluded that a GRADE (Grading of Recommendations, Assessment, Development and Evaluations) 1B strong recommendation with moderate quality of evidence supported a Mediterranean style dietary pattern for prevention of cognitive impairment [144, 145]. Furthermore, those dietary patterns may be correlated with brain volume, white matter integrity and grey matter volume, loss of which have been shown to precede cognitive decline [146].

The ketogenic diet modified with Mediterranean diet characteristics in older adults with subjective memory complaints or MCI was reported to improve memory and was associated with increased CSF Aβ₄₂ and decreased tau [147]. A recent RCT (NCT02984540) reported similar findings of favorable changes in CSF Aβ biomarkers, plus improvements in body composition and body fat distribution among older adults at risk of AD [148].

Additionally, preclinical trials on ketogenic diet reported discrepant findings: some showed less Aβ deposition and tau aggregation based on animal models of AD, but others not [149]. Systematic reviews provide some support for benefits of ketogenic diets, which may improve brain metabolism and biomarkers, and delay or ameliorate cognitive decline among patients with AD/MCI [149, 150]. However, the evidence remains limited and inconclusive especially in human studies (Supplementary Table 2) [151]. For example, in a randomized crossover trial (ACTRN12618001450202) of patients with probable AD, consuming a ketogenic diet showed only a modest and statistically insignificant trend for a beneficial change in cognition [152]. Moreover, although ketogenic diet may be feasible in mild AD and in an institutional setting [49], it was suggested impractical among community patients living with moderate AD, due to a high withdrawal rate related to increased carer burden [51].

DISCUSSION

Overall, there is limited evidence of known nutrition senotherapeutics (senolytic agents or SASP inhibitors) in AD from human clinical trials, despite promising results from several preclinical studies [62 , 154]. Factors underlying the discrepant results between trials, may be related to the bioavailability of the intervention agents and their difficulty accessing the brain [88 , 156]. For example, in clinical trials, the utilization of nutrition senotherapeutics, is greatly impeded by their poor bioavailability [37 , 158]. Possible solutions may involve nanoparticle formulation and chemical modification, by targeting individual causes of low bioavailability for senotherapeutic agents [159 –162]. Recent studies suggested encapsulation of quercetin in nanoparticles may improve its penetration through the blood-brain barrier [163] and lead to increased efficacy of delivery, and thereby ameliorate cognitive decline [62]. Similarly, novel resveratrol nano-delivery system proposed for CNS penetration was reported to enhance brain permeability in animal models, however, lack evidence in human studies [164, 165]. Although curcumin could cross the blood-brain barrier, nanoparticulation of curcumin was reported to have remarkably prolonged length of curcumin retention in the cerebral cortex and hippocampus [166]. Co-administration of a metabolism inhibitor such as piperine, to inhibit resveratrol’s fast metabolism that results in low bioavailability, has also been suggested as a promising strategy to improve the efficacy of resveratrol [167]. Treatment efficacy and CNS penetration of nutrition senotherapeutics could be improved by a combination of nanoparticles and an antioxidant environment. For example, dual-loaded nanoparticles of EGCG/ascorbic acid were reported enhance therapeutic efficacy of EGCG in AD mice model [168]. Future in-human studies are warranted.

Furthermore, bioavailability may also be impacted by multiple factors including the effects of the food matrix, endogenous factors such as dysbiosis in gut microbiota and altered secretion of digestive enzymes [155] and the background diet [169, 170]. Multiple polyphenols with varied bioavailability may act synergistically [169]. Moreover, understanding the importance of gut microbiota in the metabolism of nutrition senotherapeutics is essential [171, 172].

The optimal dosing regimen for nutrition senotherapeutic agents remain unclear [70]. Doses have varied between clinical trials. A few studies suggested intermittent dosing rather than continuous dosing (on a daily basis) to reduce potential toxicity, based on the hypothesis that senescent cells accumulate slowly over a period of weeks in the brain, and episodic elimination of senescent cells, if proven to be effective, may be adequate [33, 38]. By contrast, research that has implemented continuous dosing, with or without gradual dose escalation to higher levels, have reported positive effects on cognition and neuroinflammation [84]. Although higher dosages are generally more effective in animal experiments, evidence is lacking in humans [109]. A nonlinear dose-response relationship may exist for some agents [109, 158].

A number of key questions remain, namely: what are the differences in treatment efficacy and underlying mechanisms for nutrition senotherapeutic responses associated with intermittent versus continuous dosing; and how do low doses provided from natural food or supplements compare with high doses given as a pharmacological agent or supplement? The investigation of dose-response relationships poses a significant challenge as the determination of the appropriate dosage via assessment of pharmacokinetics such as in the CNS require invasive procedures [75]. Notwithstanding the difficulties, for future therapeutic application, pharmacokinetic and pharmacodynamic studies are critical to determine standard doses with safety and potential toxicity considerations [109].

Understanding of cellular senescence and SASP markers related to AD is still in its infancy [45]. It remains unconfirmed whether levels of SASP factors or senescence-associated biomarkers in plasma could reliably track changes of senescent cell burden in AD trials [34 , 173]. Further research is essential to develop and validate novel assays [34] in order to identify clinically relevant biomarkers shared between cellular senescence and AD across specimen types [39]. Moreover, in terms of senescent cells in the brain, it was suggested that senescent glial cells are more susceptible to senotherapeutic treatment. By contrast, senescent neurons as non-dividing postmitotic cells, may not be easily influenced by senolytics or senomorphics [174]. Future studies are warranted to investigate the underlying mechanism, as well as to examine different effects of senolytic and senomorphic agents and whether they are cell-type specific. Development of a variety of brain imaging modalities could be effectively applied such as magnetic resonance imaging (MRI) and positron emission tomography (PET) to identify and investigate pathological age-related brain changes in relation to senescent cells and SASP factors in AD trials [175]. Despite preliminary findings on changes in biomarker levels such as GFAP and IL-6 which may reflect the level of senescent cells and neuroinflammatory response [75], counter-intuitive results reported by current trials with small sample sizes [75] have complicated possible interpretations (Table 2). Future RCTs that are adequately powered are required to determine how long the changes of biomarkers in blood, in CSF, and in the brain, may be sustained post senotherapeutic treatment in AD [75]. The roles of plasma AD biomarkers, such as Aβ_1 - 40, Aβ_1 - 42, NFL, GFAP and p-Tau181, should be also explored in future research [176].

Despite limited evidence from current clinical trials, targeting cellular senescence using agents for clearance of senescent cells or inhibition of SASP factors has the potential to delay the onset or progression of AD [31]. For better understanding and effective treatment of AD, rather than relying on one sole avenue such as the Aβ antibodies based on amyloid cascade hypothesis, researchers should choose multiple pathways, based on various mechanisms jointly involved in complicated pathophysiology of AD [19, 24]. According to The Unitary Theory of Fundamental Aging Mechanisms, nine hallmarks of aging are interdependent [31 , 177]. By intervening one of the nine, the fundamental aging processes of cell senescence, which is now recognized as a key factor that associates aging with AD brains, other aging processes such as telomere attrition, mitochondrial dysfunction epigenetic alterations, mitochondrial dysfunction, and stem cell exhaustion may be greatly impacted [31, 33]. Furthermore, compared to traditional methods that direct attention to treating one medical condition at a time, targeting cellular senescence and SASP factors which created pro-inflammatory and pro-tumorigenic environments [32, 45] favorable for multiple co-morbidities with aging, may present an opportunity for management of multiple age-related including, but not limited to, AD [31, 70]. This approach could potentially lead to a reduction of polypharmacy and its related risks such as toxicity among older adults [178, 179].

Diets can affect accumulation of senescent cells [180]. A protective role of dietary patterns that are rich in known and potential nutritional senolytic agents and SASP inhibitors, such as the Mediterranean and MIND diets, have been mostly supported by recent studies for prevention of AD [143, 181]. Mediterranean diet was reported to positively impact on each hallmark of aging, which may contribute to its beneficial effects on AD risk and longevity [59]. The MIND diet, characterized by berries, nuts, olive oil and a variety of fruits, vegetables and legumes has been shown to have a strong association with better cognitive performance and brain health, also impacting on multiple hallmarks of aging [181, 182]. However, the underlying mechanisms remain unclear, as to whether the benefit to aging was due to senolytic agents and SASP inhibitors within the foods of the whole diet [140]. Although the Mediterranean and MIND diets contain polyphenols such as quercetin, resveratrol, and fisetin which have been shown to have potential as alleviators of cellular senescence and inhibitor of SASP, these diets are also rich in nutritional components that improve cellular antioxidant and inflammatory homeostasis [58, 140]. In addition, synergies between numerous nutrients and bioactive components in a diet may play an important role to prevent or slow cognitive decline [58], and the complexity of multiple interactions between nutrients should not be overlooked [183]. On the other hand, dietary components and nutrition senotherapeutic agents are also critical in mediating the effects of those diets [172], and should be studied individually, as well as in combinations of whole dietary patterns, through the perspective of cellular senescence [45]. Further studies are warranted to examine the effects of the entire dietary patterns on prevalence of senescent cells in the brain, and for better understanding of cell-type-specific senescence.

We note that current collection of senotherapeutic agents is limited, doubtless many more will be discovered as research advances in future [46 , 177]. Rather than interventions to eliminate senescent cells that are dynamic and heterogeneous [184], multiple senotherapeutic approaches that inhibit SASP activity may be promising in preventing AD [45]. Secondly, in targeting cellular senescence as a fundamental aging process, it is important to carefully balance between benefits and potential risks. Although the majority of studies reported minor adverse events (Table 2), potential side effects have not been yet fully explored and understood [33]. Thirdly, senotherapeutics may be considered a preventative approach in AD, however, rather than supplementation only, delaying the process of cell senescence with natural foods and healthy diets is of paramount importance [185], as healthy diets contain many different biologically active molecules acting synergistically and on diverse molecular pathways. Fourthly, in future study design, longer trial durations are required. Current trial lengths varied between 12 weeks to 2 years (see Table 2 for details); majority fell below the suggestion of at least 18-months to detect cognitive decline in placebo groups, based on the estimated rate of disease progression in mild to moderate AD [186]. Finally, in order to identify mechanistic actions, the association between nutrition senotherapy and cognitive health, with respect to hallmark AD biomarkers in CSF, in blood, and in brain, should be further investigated [187, 188]; a biomarker-based and genetics-based selection of participants are highly recommended [149, 189]; brain imaging modalities could facilitate development of effective disease-modifying therapies and preventative dietary strategies [190]. Global collaborations between researchers should be established to facilitate and accelerate identification, development, investigation of senotherapy, as well as translation into clinical trials and finally clinical practice [31]. In the future, with adequate evidence supported by emerging research, precision nutrition with individualized dietary recommendations, considering senotherapeutics from natural foods or supplementation, may be possible for prevention and management of AD [140].

CONCLUSION

This review has summarized the scientific literature on the role of known and potential nutrition senotherapeutic agents and related dietary patterns in AD. Pre-clinical studies reported promising results indicative of neuroprotective effects; however, evidence from in-human trials remain limited and inconclusive. While dosing regimen, long term impacts and cytotoxic effects of senotherapeutic agents remain unclear, delaying the onset or progression of AD with natural foods and healthy diets is of paramount importance. Future research is warranted to investigate the efficacy and safety of nutrition senotherapy in AD and provide better understanding of the underlying mechanisms. Development of novel assays is needed, and a variety of brain imaging modalities could be effectively applied to examine pathological brain changes. Nutrition senotherapeutic agents should be studied both individually and within a dietary pattern, through the perspective of cellular senescence and AD, with respect to senescence-associated biomarkers and AD biomarkers in CSF, in blood, and in brain.

AUTHOR CONTRIBUTIONS

Xi Chen (Conceptualization; Methodology; Project administration; Resources; Software; Writing – original draft; Writing – review & editing); Karen Walton (Writing – review & editing); Karen Charlton (Conceptualization; Investigation; Writing – review & editing); Henry Brodaty (Conceptualization; Investigation; Methodology; Supervision; Writing – review & editing).

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgement to report.

FUNDING

The authors have no funding to report.

CONFLICT OF INTEREST

Henry Brodaty is or has been an advisory board member or consultant to Biogen, Eisai, Eli Lilly, Medicines Australia, Roche and Skin2Neuron. He is a Medical/Clinical Advisory Board member for Montefiore Homes and Cranbrook Care.

All other authors have no conflict of interest to report.

The supplementary material is available in the electronic version of this article: .

References

Livingston

, Sommerlad

, Orgeta

, Costafreda

, Huntley

, Ames

, Ballard

, Banerjee

, Burns

, Cohen-Mansfield

(2017) Dementia prevention, intervention, and care. Lancet390, 2673–2734.

Dementia Statistics, Alzheimer’s Disease International, https://www.alzint.org/about/dementia-facts-figures/dementia-statistics/.

Ibanez

, Parra

, Butler

(2021) The Latin America and the Caribbean Consortium on Dementia (LAC-CD): From networking to research to implementation science. J Alzheimers Dis82, S379–S394.

Livingston

, Huntley

, Sommerlad

, Ames

, Ballard

, Banerjee

, Brayne

, Burns

, Cohen-Mansfield

, Cooper

(2020) Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet396, 413–446.

Long

, Benoist

, Weidner

(2023) World Alzheimer Report 2023: Reducing dementia risk: Never too early, never too late. Alzheimer’s Disease International, London, England.

Alzheimer’s Association(2024) 2024 Alzheimer’s disease facts and figures. Alzheimers Dement20, 3708–3821.

Bishop

, Lu

, Yankner

(2010) Neural mechanisms of ageing and cognitive decline. Nature464, 529–535.

Ballard

, Gauthier

, Corbett

, Brayne

, Aarsland

, Jones

(2011) Alzheimer’s disease. Lancet377, 1019–1031.

Hyman

, Phelps

, Beach

, Bigio

, Cairns

, Carrillo

, Dickson

, Duyckaerts

, Frosch

, Masliah

, Mirra

, Nelson

, Schneider

, Thal

, Thies

, Trojanowski

, Vinters

, Montine

(2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement8, 1–13.

10.

Montine

, Phelps

, Beach

, Bigio

, Cairns

, Dickson

, Duyckaerts

, Frosch

, Masliah

, Mirra

, Nelson

, Schneider

, Thal

, Trojanowski

, Vinters

, Hyman

(2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: A practical approach. Acta Neuropathol123, 1–11.

11.

Naylor

, Baker

, van Deursen

(2013) Senescent cells: A novel therapeutic target for aging and age-related diseases. Clin Pharmacol Ther93, 105–116.

12.

Childs

, Gluscevic

, Baker

, Laberge

, Marquess

, Dananberg

, van Deursen

(2017) Senescent cells: An emerging target for diseases of ageing. Nat Rev Drug Discov16, 718–735.

13.

Carone

, Asgharian

, Jewell

(2014) Estimating the lifetime risk of dementia in the Canadian elderly population using cross-sectional cohort survival data. J Am Stat Assoc109, 24–35.

14.

Niu

, Álvarez-Álvarez

, Guillén-Grima

, Aguinaga-Ontoso

(2017) Prevalence and incidence of Alzheimer’s disease in Europe: A meta-analysis. Neurologia32, 523–532.

15.

Kepp

, Robakis

, Høilund-Carlsen

, Sensi

, Vissel

(2023) The amyloid cascade hypothesis: An updated critical review. Brain146, 3969–3990.

16.

Van Dyck

, Swanson

, Aisen

, Bateman

, Chen

, Gee

, Kanekiyo

, Li

, Reyderman

, Cohen

(2023) Lecanemab in early Alzheimer’s disease. N Engl J Med388, 9–21.

17.

Budd Haeberlein

, Aisen

, Barkhof

, Chalkias

, Chen

, Cohen

, Dent

, Hansson

, Harrison

, von Hehn

, Iwatsubo

, Mallinckrodt

, Mummery

, Muralidharan

, Nestorov

, Nisenbaum

, Rajagovindan

, Skordos

, Tian

, van Dyck

, Vellas

, Wu

, Zhu

, Sandrock

(2022) Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease. J Prev Alzheimers Dis9, 197–210.

18.

Sims

, Zimmer

, Evans

, Lu

, Ardayfio

, Sparks

, Wessels

, Shcherbinin

, Wang

, Monkul Nery

, Collins

, Solomon

, Salloway

, Apostolova

, Hansson

, Ritchie

, Brooks

, Mintun

, Skovronsky

, TRAILBLAZER-ALZ 2 Investigators.(2023) Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA330, 512–527.

19.

Herrup

(2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci18, 794–799.

20.

Price

, Morris

(1999) Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol45, 358–368.

21.

Knopman

, Parisi

, Salviati

, Floriach-Robert

, Boeve

, Ivnik

, Smith

, Dickson

, Johnson

, Petersen

(2003) Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol62, 1087–1095.

22.

Sevigny

, Chiao

, Bussière

, Weinreb

, Williams

, Maier

, Dunstan

, Salloway

, Chen

, Ling

(2017) Addendum: The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature546, 564–564.

23.

Cummings

, Aisen

, Lemere

, Atri

, Sabbagh

, Salloway

(2021) Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimers Res Ther13, 98.

24.

Kurkinen

, Fułek

, Beszłej

, Kurpas

, Leszek

(2023) The amyloid cascade hypothesis in Alzheimer’s disease: Should we change our thinking?Biomolecules13, 453.

25.

Lao

, Zhang

, Luan

, Zhang

, Gou

(2021) Therapeutic strategies targeting amyloid-β receptors and transporters in Alzheimer’s disease. J Alzheimers Dis79, 1429–1442.

26.

Imbimbo

, Lucca

, Watling

(2020) Can anti–β-amyloid monoclonal antibodies work in autosomal dominant Alzheimer disease?Neurol Genet7, e535.

27.

, Pirtskhalava

, Farr

, Weigand

, Palmer

, Weivoda

, Inman

, Ogrodnik

, Hachfeld

, Fraser

, Onken

, Johnson

, Verzosa

, Langhi

LGP

, Weigl

, Giorgadze

, LeBrasseur

, Miller

, Jurk

, Singh

, Allison

, Ejima

, Hubbard

, Ikeno

, Cubro

, Garovic

, Hou

, Weroha

, Robbins

, Niedernhofer

, Khosla

, Tchkonia

, Kirkland

(2018) Senolytics improve physical function and increase lifespan in old age. Nat Med24, 1246–1256.

28.

Romashkan

, Chang

, Hadley

(2021) National Institute on Aging Workshop: Repurposing drugs or dietary supplements for their senolytic or senomorphic effects: Considerations for clinical trials. J Gerontol A Biol Sci Med Sci76, 1144–1152.

29.

Gonzales

, Krishnamurthy

, Garbarino

, Daeihagh

, Gillispie

, Deep

, Craft

, Orr

(2021) A geroscience motivated approach to treat Alzheimer’s disease: Senolytics move to clinical trials. Mech Ageing Dev200, 111589.

30.

Calcinotto

, Kohli

, Zagato

, Pellegrini

, Demaria

, Alimonti

(2019) Cellular senescence: Aging, cancer, and injury. Physiol Rev99, 1047–1078.

31.

Wissler Gerdes

, Misra

, Netto

JME

, Tchkonia

, Kirkland

(2021) Strategies for late phase preclinical and early clinical trials of senolytics. Mech Ageing Dev200, 111591.

32.

Diwan

, Sharma

(2022) Nutritional components as mitigators of cellular senescence in organismal aging: A comprehensive review. Food Sci Biotechnol31, 1089–1109.

33.

Kirkland

, Tchkonia

(2020) Senolytic drugs: From discovery to translation. J Intern Med288, 518–536.

34.

Kirkland

, Tchkonia

(2017) Cellular senescence: A translational perspective. EBioMedicine21, 21–28.

35.

Khosla

, Farr

, Tchkonia

, Kirkland

(2020) The role of cellular senescence in ageing and endocrine disease. Nat Rev Endocrinol16, 263–275.

36.

Di Micco

, Krizhanovsky

, Baker

, d’Adda di Fagagna

(2021) Cellular senescence in ageing: From mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol22, 75–95.

37.

Gonzales

, Garbarino

, Marques Zilli

, Petersen

, Kirkland

, Tchkonia

, Musi

, Seshadri

, Craft

, Orr

(2022) Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD): A pilot clinical trial. J Prev Alzheimers Dis9, 22–29.

38.

Musi

, Valentine

, Sickora

, Baeuerle

, Thompson

, Shen

, Orr

(2018) Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell17, e12840.

39.

Tuttle

CSL

, Waaijer

MEC

, Slee-Valentijn

, Stijnen

, Westendorp

, Maier

(2020) Cellular senescence and chronological age in various human tissues: A systematic review and meta-analysis. Aging Cell19, e13083.

40.

Bussian

, Aziz

, Meyer

, Swenson

, van Deursen

, Baker

(2018) Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature562, 578–582.

41.

Chinta

, Woods

, Rane

, Demaria

, Campisi

, Andersen

(2015) Cellular senescence and the aging brain. Exp Gerontol68, 3–7.

42.

Wong

, Chow

(2023) DNA damage response-associated cell cycle re-entry and neuronal senescence in brain aging and Alzheimer’s disease. J Alzheimers Dis94, S429–s451.

43.

Tan

FCC

, Hutchison

, Eitan

, Mattson

(2014) Are there roles for brain cell senescence in aging and neurodegenerative disorders?Biogerontology15, 643–660.

44.

Lin

, Kapoor

, Gu

, Chow

, Peng

, Zhao

, Tang

(2020) Contributions of DNA damage to Alzheimer’s disease. Int J Mol Sci21, 1666.

45.

Guerrero

, De

Strooper B

, Arancibia-Cárcamo

(2021) Cellular senescence at the crossroads of inflammation and Alzheimer’s disease. Trends Neurosci44, 714–727.

46.

, Qin

, Feng

, Hu

, Sun

, He

, Zhang

(2019) Emerging senolytic agents derived from natural products. Mech Ageing Dev181, 1–6.

47.

Birch

, Gil

(2020) Senescence and the SASP: Many therapeutic avenues. Genes Dev34, 1565–1576.

48.

Efimova

, Takahashi

, Shamsi

, Wu

, Labay

, Ulanovskaya

, Weichselbaum

, Kozmin

, Kron

(2016) Linking cancer metabolism to DNA repair and accelerated senescence. Mol Cancer Res14, 173–184.

49.

Hersant

, Grossberg

(2022) The ketogenic diet and Alzheimer’s disease. J Nutr Health Aging26, 606–614.

50.

Lim

, Park

, Kim

(2015) Effects of flavonoids on senescence-associated secretory phenotype formation from bleomycin-induced senescence in BJ fibroblasts. Biochem Pharmacol96, 337–348.

51.

Taylor

, Sullivan

, Mahnken

, Burns

, Swerdlow

(2018) Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer’s disease. Alzheimers Dement (N Y)4, 28–36.

52.

Gao

, Wu

, He

, Zhu

, Li

, Liu

(2020) Anti-aging effects of Ribes meyeri anthocyanins on neural stem cells and aging mice. Aging (Albany NY)12, 17738–17753.

53.

Molino

, Dossena

, Buonocore

, Ferrari

, Venturini

, Ricevuti

, Verri

(2016) Polyphenols in dementia: From molecular basis to clinical trials. Life Sci161, 69–77.

54.

Holland

, Agarwal

, Wang

, Dhana

, Leurgans

, Shea

, Booth

, Rajan

, Schneider

, Barnes

(2023) Association of dietary intake of flavonols with changes in global cognition and several cognitive abilities. Neurology100, e694–e702.

55.

Sharma

(2020) Perspectives of the potential implications of polyphenols in influencing the interrelationship between oxi-inflammatory stress, cellular senescence and immunosenescence during aging. Trends Food Sci Technol98, 41–52.

56.

Jayasena

, Poljak

, Smythe

, Braidy

, Münch

, Sachdev

(2013) The role of polyphenols in the modulation of sirtuins and other pathways involved in Alzheimer’s disease. Ageing Res Rev12, 867–883.

57.

Sharma

, Padwad

(2020) Nutraceuticals-based immunotherapeutic concepts and opportunities for the mitigation of cellular senescence and aging: A narrative review. Ageing Res Rev63, 101141.

58.

Chen

, Maguire

, Brodaty

, O’Leary

(2019) Dietary patterns and cognitive health in older adults: A systematic review. J Alzheimers Dis67, 583–619.

59.

Shannon

, Ashor

, Scialo

, Saretzki

, Martin-Ruiz

, Lara

, Matu

, Griffiths

, Robinson

, Lillà

, Stevenson

, Stephan

BCM

, Minihane

, Siervo

, Mathers

(2021) Mediterranean diet and the hallmarks of ageing. Eur J Clin Nutr75, 1176–1192.

60.

Di Petrillo

, Orrù

, Fais

, Fantini

(2022) Quercetin and its derivates as antiviral potentials: A comprehensive review. Phytother Res36, 266–278.

61.

Zhu

, Tchkonia

, Pirtskhalava

, Gower

, Ding

, Giorgadze

, Palmer

, Ikeno

, Hubbard

, Lenburg

, O’Hara

, LaRusso

, Miller

, Roos

, Verzosa

, LeBrasseur

, Wren

, Farr

, Khosla

, Stout

, McGowan

, Fuhrmann-Stroissnigg

, Gurkar

, Zhao

, Colangelo

, Dorronsoro

, Ling

, Barghouthy

, Navarro

, Sano

, Robbins

, Niedernhofer

, Kirkland

(2015) The Achilles’ heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell14, 644–658.

62.

Zhang

X-W

, Chen

J-Y

, Ouyang

, Lu

J-H

(2020) Quercetin in animal models of Alzheimer’s disease: A systematic review of preclinical studies. Int J Mol Sci21, 493.

63.

Aggarwal

, Sharma

, Khera

, Sandhir

, Rishi

(2020) Quercetin alleviates cognitive decline in ovariectomized mice by potentially modulating histone acetylation homeostasis. J Nutr Biochem84, 108439.

64.

, Chen

F-J

, Yang

W-L

, Qiao

H-Z

, Zhang

S-J

(2021) Quercetin improves cognitive disorder in aging mice by inhibiting NLRP3 inflammasome activation. Food Funct12, 717–725.

65.

Jakaria

, Azam

, Jo

S-H

, Kim

I-S

, Dash

, Choi

D-K

(2019) Potential therapeutic targets of quercetin and its derivatives: Its role in the therapy of cognitive impairment. J Clin Med8, 1789.

66.

Khan

, Ullah

, Aschner

, Cheang

, Akkol

(2019) Neuroprotective effects of quercetin in Alzheimer’s disease. Biomolecules10, 59.

67.

Yang

, Zhou

, Wang

, Zhong

X-H

, Shen

Q-L

, Zhang

X-J

, Li

R-Y

, Chen

L-H

, Zhang

Y-H

, Wan

(2020) Quercetin is protective against short-term dietary advanced glycation end products intake induced cognitive dysfunction in aged ICR mice. J Food Biochem44, e13164.

68.

Grewal

, Singh

, Sharma

, Singh

, Rahman

, Najda

, Walasek-Janusz

, Kamel

, Albadrani

, Akhtar

, Saleem

, Abdel-Daim

(2021) Mechanistic insights and perspectives involved in neuroprotective action of quercetin. Biomed Pharmacother140, 111729.

69.

Costa

, Garrick

, Roquè

, Pellacani

(2016) Mechanisms of neuroprotection by quercetin: Counteracting oxidative stress and more, Oxid Med Cell Longev2016, 2986796 .

70.

Song

, Tchkonia

, Jiang

, Kirkland

, Sun

(2020) Targeting senescent cells for a healthier aging: Challenges and opportunities. Adv Sci (Weinh)7, 2002611.

71.

Zhu

, Tchkonia

, Fuhrmann-Stroissnigg

, Dai

, Ling

, Stout

, Pirtskhalava

, Giorgadze

, Johnson

, Giles

, Wren

, Niedernhofer

, Robbins

, Kirkland

(2016) Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell15, 428–435.

72.

Krzystyniak

, Wesierska

, Petrazzo

, Gadecka

, Dudkowska

, Bielak-Zmijewska

, Mosieniak

, Figiel

, Wlodarczyk

, Sikora

(2022) Combination of dasatinib and quercetin improves cognitive abilities in aged male Wistar rats, alleviates inflammation and changes hippocampal synaptic plasticity and histone H3 methylation profile. Aging (Albany NY)14, 572–595.

73.

Zhang

, Kishimoto

, Grammatikakis

, Gottimukkala

, Cutler

, Zhang

, Abdelmohsen

, Bohr

, Misra Sen

, Gorospe

, Mattson

(2019) Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci22, 719–728.

74.

Ogrodnik

, Evans

, Fielder

, Victorelli

, Kruger

, Salmonowicz

, Weigand

, Patel

, Pirtskhalava

, Inman

, Johnson

, Dickinson

, Rocha

, Schafer

, Zhu

, Allison

, von Zglinicki

, LeBrasseur

, Tchkonia

, Neretti

, Passos

, Kirkland

, Jurk

(2021) Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell20, e13296.

75.

Gonzales

, Garbarino

, Kautz

, Palavicini

, Lopez-Cruzan

, Dehkordi

, Mathews

, Zare

, Xu

, Zhang

, Franklin

, Habes

, Craft

, Petersen

, Tchkonia

, Kirkland

, Salardini

, Seshadri

, Musi

, Orr

(2023) Senolytic therapy in mild Alzheimer’s disease: A phase 1 feasibility trial. Nat Med29, 2481–2488.

76.

Nishimura

, Ohkawara

, Nakagawa

, Muro

, Sato

, Satoh

, Kobori

, Nishihira

(2017) A randomized, double-blind, placebo-controlled study evaluating the effects of quercetin-rich onion on cognitive function in elderly subjects. Funct Foods Health Dis7, 353–374.

77.

Nishihira

, Nishimura

, Kurimoto

, Kagami-Katsuyama

, Hattori

, Nakagawa

, Muro

, Kobori

(2021) The effect of 24-week continuous intake of quercetin-rich onion on age-related cognitive decline in healthy elderly people: A randomized, double-blind, placebo-controlled, parallel-group comparative clinical trial. J Clin Biochem Nutr69, 203–215.

78.

Nakamura

, Watanabe

, Tanaka

, Nishihira

, Murayama

(2022) Effect of quercetin glycosides on cognitive functions and cerebral blood flow: A randomized, double-blind, and placebo-controlled study. Eur Rev Med Pharmacol Sci26, 8700–8712.

79.

Chen

J-Y

, Zhu

, Zhang

, OuYang

, Lu

J-H

(2019) Resveratrol in experimental Alzheimer’s disease models: A systematic review of preclinical studies. Pharmacol Res150, 104476.

80.

Pasinetti

, Wang

, Ho

, Zhao

, Dubner

(2015) Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochim Biophys Acta1852, 1202–1208.

81.

Sawda

, Moussa

, Turner

(2017) Resveratrol for Alzheimer’s disease. Ann N Y Acad Sci1403, 142–149.

82.

Marx

, Kelly

, Marshall

, Cutajar

, Annois

, Pipingas

, Tierney

, Itsiopoulos

(2018) Effect of resveratrol supplementation on cognitive performance and mood in adults: A systematic literature review and meta-analysis of randomized controlled trials. Nutr Rev76, 432–443.

83.

Turner

, Thomas

, Craft

, Dyck

CHv

, Mintzer

, Reynolds

, Brewer

, Rissman

, Raman

, Aisen

, Study FtAsDC (2015) A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology85, 1383–1391.

84.

Moussa

, Hebron

, Huang

, Ahn

, Rissman

, Aisen

, Turner

(2017) Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. J Neuroinflammation14, 1.

85.

, Li

, Chen

, Xu

, Li

, Gui

(2021) Neuroprotective effect of trans-resveratrol in mild to moderate Alzheimer disease: A randomized, double-blind trial. Neurol Ther10, 905–917.

86.

Zhu

, Grossman

, Neugroschl

, Parker

, Burden

, Luo

, Sano

(2018) A randomized, double-blind, placebo-controlled trial of resveratrol with glucose and malate (RGM) to slow the progression of Alzheimer’s disease: A pilot study. Alzheimers Dement (N Y)4, 609–616.

87.

Patel

, Scott

, Brown

, Gescher

, Steward

, Brown

(2011) Clinical trials of resveratrol. Ann N Y Acad Sci1215, 161–169.

88.

Cascella

, Bimonte

, Muzio

, Schiavone

, Cuomo

(2017) The efficacy of Epigallocatechin-3-gallate (green tea) in the treatment of Alzheimer’s disease: An overview of pre-clinical studies and translational perspectives in clinical practice. Infect Agent Cancer12, 36.

89.

Walker

, Klakotskaia

, Ajit

, Weisman

, Wood

, Sun

, Serfozo

, Simonyi

, Schachtman

(2015) Beneficial effects of dietary EGCG and voluntary exercise on behavior in an Alzheimer’s disease mouse model. J Alzheimers Dis44, 561–572.

90.

Kumar

, Sharma

, Kumari

, Gulati

, Padwad

, Sharma

(2019) Epigallocatechin gallate suppresses premature senescence of preadipocytes by inhibition of PI3K/Akt/mTOR pathway and induces senescent cell death by regulation of Bax/Bcl-2 pathway. Biogerontology20, 171–189.

91.

Payne

, Nahashon

, Taka

, Adinew

, Soliman

KFA

(2022) Epigallocatechin-3-gallate (EGCG): New therapeutic perspectives for neuroprotection, aging, and neuroinflammation for the modern age. Biomolecules12, 371.

92.

Zhang

, Zhu

, Chen

, OuYang

, Lu

(2020) The pharmacological activity of epigallocatechin-3-gallate (EGCG) on Alzheimer’s disease animal model: A systematic review. Phytomedicine79, 153316.

93.

Youn

, Ho

C-T

, Jun

(2022) Multifaceted neuroprotective effects of (-)-epigallocatechin-3-gallate (EGCG) in Alzheimer’s disease: An overview of pre-clinical studies focused on β-amyloid peptide. Food Sci Hum Wellness11, 483–493.

94.

Huang

, Cheng

, Yang

, Chang

, Ho

, Chuang

, Li

, Huang

, Lin

, Shen

, Yu

, Kang

, Lin

, Chen

(2021) Intra-articular injection of (-)-epigallocatechin 3-gallate (EGCG) ameliorates cartilage degeneration in guinea pigs with spontaneous osteoarthritis. Antioxidants (Basel)10, 178.

95.

Lorenzo

, Cuenca

, Operto

, Falcon

, Puig-Pijoan

, Forcano

, Piera

, Boronat

, Knezevic

, de Toma

, Soldevila-Domenech

, Fauria

, Molinuevo

, Gispert

, Torre

Rdl

, Group

(2023) Cognitive function and brain structure correlates in individuals with subjective cognitive decline: Voxel-based morphometry results from a lifestyle intervention to prevent Alzheimer’s disease (PENSA study). Alzheimers Dement19, e064849.

96.

Sakurai

, Shen

, Ezaki

, Inamura

, Fukushima

, Masuoka

, Hisatsune

(2020) Effects of Matcha green tea powder on cognitive functions of community-dwelling elderly individuals. Nutrients12, 3639.

97.

Baba

, Inagaki

, Nakagawa

, Kaneko

, Kobayashi

, Takihara

(2020) Effect of daily intake of green tea catechins on cognitive function in middle-aged and older subjects: A randomized, placebo-controlled study. Molecules25, 4265.

98.

Zia

, Farkhondeh

, Pourbagher-Shahri

, Samarghandian

(2021) The role of curcumin in aging and senescence: Molecular mechanisms. Biomed Pharmacother134, 111119.

99.

, He

, Zhang

, Zheng

, Zhou

(2019) The curcumin analog EF24 is a novel senolytic agent. Aging (Albany NY)11, 771.

100.

Matacchione

, Gurău

, Silvestrini

, Tiboni

, Mancini

, Valli

, Rippo

, Recchioni

, Marcheselli

, Carnevali

, Procopio

, Casettari

, Olivieri

(2021) Anti-SASP and anti-inflammatory activity of resveratrol, curcumin and β-caryophyllene association on human endothelial and monocytic cells. Biogerontology22, 297–313.

101.

, Chiam

, Lee

, Chua

, Lim

, Kua

(2006) Curry consumption and cognitive function in the elderly. Am J Epidemiol164, 898–906.

102.

Tang

, Taghibiglou

(2017) The mechanisms of action of curcumin in Alzheimer’s disease. J Alzheimers Dis58, 1003–1016.

103.

Mishra

, Palanivelu

(2008) The effect of curcumin (turmeric) on Alzheimer’s disease: An overview. Ann Indian Acad Neurol11, 13–19.

104.

Wang

, Yin

, Wang

, Shuboy

, Lou

, Han

, Zhang

, Li

(2013) Curcumin as a potential treatment for Alzheimer’s disease: A study of the effects of curcumin on hippocampal expression of glial fibrillary acidic protein. Am J Chin Med41, 59–70.

105.

Garcia-Alloza

, Borrelli

, Rozkalne

, Hyman

, Bacskai

(2007) Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem102, 1095–1104.

106.

, Yang

, Rosario

, Ubeda

, Beech

, Gant

, Chen

, Hudspeth

, Chen

, Zhao

, Vinters

, Frautschy

, Cole

(2009) Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: Suppression by omega-3 fatty acids and curcumin. J Neurosci29, 9078–9089.

107.

Yang

, Lim

, Begum

, Ubeda

, Simmons

, Ambegaokar

, Chen

, Kayed

, Glabe

, Frautschy

, Cole

(2005) Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem280, 5892–5901.

108.

Lin

, Li

, Zhang

, Yuan

, Chen

C-h

, Li

(2020) Synergic effects of berberine and curcumin on improving cognitive function in an Alzheimer’s disease mouse model. Neurochem Res45, 1130–1141.

109.

Voulgaropoulou

, van Amelsvoort

, Prickaerts

, Vingerhoets

(2019) The effect of curcumin on cognition in Alzheimer’s disease and healthy aging: A systematic review of pre-clinical and clinical studies. Brain Res1725, 146476.

110.

Ringman

, Frautschy

, Teng

, Begum

, Bardens

, Beigi

, Gylys

, Badmaev

, Heath

, Apostolova

, Porter

, Vanek

, Marshall

, Hellemann

, Sugar

, Masterman

, Montine

, Cummings

, Cole

(2012) Oral curcumin for Alzheimer’s disease: Tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Res Ther4, 43.

111.

Yang

, Jin

G-F

, Ren

D-D

, Luo

S-J

, Zhou

T-H

(2010) Neuro-protective mechanism of isoflavones on senescence-accelerated mice. Chin J Nat Med8, 280–284.

112.

Cui

, Birru

, Snitz

, Ihara

, Kakuta

, Lopresti

, Aizenstein

, Lopez

, Mathis

, Miyamoto

(2020) Effects of soy isoflavones on cognitive function: A systematic review and meta-analysis of randomized controlled trials. Nutr Rev78, 134–144.

113.

Henderson

, John

JAS

, Hodis

, Kono

, McCleary

, Franke

, Mack

(2012) Long-term soy isoflavone supplementation and cognition in women: A randomized, controlled trial. Neurology78, 1841–1848.

114.

Svensson

, Sawada

, Mimura

, Nozaki

, Shikimoto

, Tsugane

(2023) Midlife intakes of the isoflavone genistein and soy and the risk of late-life cognitive impairment: The JPHC Saku Mental Health Study. J Epidemiol33, 342–349.

115.

Gleason

, Carlsson

, Barnet

, Meade

, Setchell

, Atwood

, Johnson

, Ries

, Asthana

(2009) A preliminary study of the safety, feasibility and cognitive efficacy of soy isoflavone supplements in older men and women. Age Ageing38, 86–93.

116.

Gleason

, Fischer

, Dowling

, Setchell

, Atwood

, Carlsson

, Asthana

(2015) Cognitive effects of soy isoflavones in patients with Alzheimer’s disease. J Alzheimers Dis47, 1009–1019.

117.

Dubois

, Feldman

, Jacova

, Hampel

, Molinuevo

, Blennow

, DeKosky

, Gauthier

, Selkoe

, Bateman

, Cappa

, Crutch

, Engelborghs

, Frisoni

, Fox

, Galasko

, Habert

, Jicha

, Nordberg

, Pasquier

, Rabinovici

, Robert

, Rowe

, Salloway

, Sarazin

, Epelbaum

, de Souza

, Vellas

, Visser

, Schneider

, Stern

, Scheltens

, Cummings

(2014) Advancing research diagnostic criteria for Alzheimer’s disease: The IWG-2 criteria. Lancet Neurol13, 614–629.

118.

Viña

, Escudero

, Baquero

, Cebrián

, Carbonell-Asíns

, Muñoz

, Satorres

, Meléndez

, Ferrer-Rebolleda

, Cózar-Santiago

MDP

, Santabárbara-Gómez

, Jové

, Pamplona

, Tarazona-Santabalbina

, Borrás

(2022) Genistein effect on cognition in prodromal Alzheimer’s disease patients. The GENIAL clinical trial. Alzheimers Res Ther14, 164.

119.

Ammar

, Trabelsi

, Müller

, Bouaziz

, Boukhris

, Glenn

, Bott

, Driss

, Chtourou

, Müller

, Hökelmann

(2020) The effect of (poly)phenol-rich interventions on cognitive functions and neuroprotective measures in healthy aging adults: A systematic review and meta-analysis. J Clin Med9, 835.

120.

Suresh

, Begum

, Singh

, V

(2022) Anthocyanin as a therapeutic in Alzheimer’s disease: A systematic review of preclinical evidences. Ageing Res Rev76, 101595.

121.

Ahles

, Joris

, Plat

(2021) Effects of berry anthocyanins on cognitive performance, vascular function and cardiometabolic risk markers: A systematic review of randomized placebo-controlled intervention studies in humans. Int J Mol Sci22, 6842.

122.

Kent

, Charlton

, Netzel

, Fanning

(2017) Food-based anthocyanin intake and cognitive outcomes in human intervention trials: A systematic review. J Hum Nutr Diet30, 260–274.

123.

Krikorian

, Kalt

, McDonald

, Shidler

, Summer

, Stein

(2020) Cognitive performance in relation to urinary anthocyanins and their flavonoid-based products following blueberry supplementation in older adults at risk for dementia. J Funct Foods64, 103667.

124.

Kent

, Charlton

, Roodenrys

, Batterham

, Potter

, Traynor

, Gilbert

, Morgan

, Richards

(2017) Consumption of anthocyanin-rich cherry juice for 12 weeks improves memory and cognition in older adults with mild-to-moderate dementia. Eur J Nutr56, 333–341.

125.

do Rosario

, Fitzgerald

, Broyd

, Paterson

, Roodenrys

, Thomas

, Bliokas

, Potter

, Walton

, Weston–Green

, Yousefi

, Williams

, Wright

IMR

, Charlton

(2021) Food anthocyanins decrease concentrations of TNF-α in older adults with mild cognitive impairment: A randomized, controlled, double blind clinical trial. Nutr Metab Cardiovasc Dis31, 950–960.

126.

Aarsland

, Khalifa

, Bergland

, Soennesyn

, Oppedal

, Holteng

LBA

, Oesterhus

, Nakling

, Jarholm

, de Lucia

, Fladby

, Brooker

, Dalen

, Ballard

(2023) A randomised placebo-controlled study of purified anthocyanins on cognition in individuals at increased risk for dementia. Am J Geriatr Psychiatry31, 141–151.

127.

Miller

, Hamilton

, Joseph

, Shukitt-Hale

(2018) Dietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trial. Eur J Nutr57, 1169–1180.

128.

Charlton

, Chenoweth

, Ostaszkiewicz

, Xiao

, Laver

, Bell

(2022) World-class projects funded by DCRC. Aust J Dement Care11, 34.

129.

Chiang

, Chan

, Chu

, Wen

(2015) Fisetin ameliorated photodamage by suppressing the mitogen-activated protein kinase/matrix metalloproteinase pathway and nuclear factor-κB pathways. J Agric Food Chem63, 4551–4560.

130.

Elsallabi

, Patruno

, Pesce

, Cataldi

, Carradori

, Gallorini

(2022) Fisetin as a senotherapeutic agent: Biopharmaceutical properties and crosstalk between cell senescence and neuroprotection. Molecules27, 738.

131.

Maher

(2020) Preventing and treating neurological disorders with the flavonol fisetin. Brain Plast6, 155–166.

132.

Ahmad

, Ali

, Park

, Badshah

, Rehman

, Kim

(2017) Neuroprotective effect of fisetin against amyloid-beta-induced cognitive/synaptic dysfunction, neuroinflammation, and neurodegeneration in adult mice. Mol Neurobiol54, 2269–2285.

133.

Wang

, He

, Rayman

, Zhang

(2021) Prospective selective mechanism of emerging senolytic agents derived from flavonoids. J Agric Food Chem69, 12418–12423.

134.

Zhu

, Doornebal

, Pirtskhalava

, Giorgadze

, Wentworth

, Fuhrmann-Stroissnigg

, Niedernhofer

, Robbins

, Tchkonia

, Kirkland

(2017) New agents that target senescent cells: The flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY)9, 955.

135.

Yousefzadeh

, Zhu

, McGowan

, Angelini

, Fuhrmann-Stroissnigg

, Xu

, Ling

, Melos

, Pirtskhalava

, Inman

, McGuckian

, Wade

, Kato

, Grassi

, Wentworth

, Burd

, Arriaga

, Ladiges

, Tchkonia

, Kirkland

, Robbins

, Niedernhofer

(2018) Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine36, 18–28.

136.

Xiao

, Lu

, Wu

, Yang

, Chen

, Zhong

, Eliezer

, Tan

, Wu

(2021) Fisetin inhibits tau aggregation by interacting with the protein and preventing the formation of β-strands. Int J Biol Macromol178, 381–393.

137.

Sloan

, Wall

, Yeung

, Feng

, Provenzano

, Schroeter

, Lauriola

, Brickman

, Small

(2021) Insights into the role of diet and dietary flavanols in cognitive aging: Results of a randomized controlled trial. Sci Rep11, 3837.

138.

Suominen

, Laaksonen

MML

, Salmenius-Suominen

, Kautiainen

, Hongisto

, Tuukkanen

, Jyväkorpi

, Pitkälä

(2020) The short-term effect of dark chocolate flavanols on cognition in older adults: A randomized controlled trial (FlaSeCo). Exp Gerontol136, 110933.

139.

Tsolaki

, Lazarou

, Kozori

, Petridou

, Tabakis

, Lazarou

, Karakota

, Saoulidis

, Melliou

, Magiatis

(2020) A randomized clinical trial of Greek high phenolic early harvest extra virgin olive oil in mild cognitive impairment: The MICOIL pilot study. J Alzheimers Dis78, 801–817.

140.

Chen

, Brodaty

, O’Leary

(2022) Nutrition senolytics - illusion or reality for cognitive ageing?Curr Opin Clin Nutr Metab Care25, 7–28.

141.

Chen

, Liu

, Sachdev

, Kochan

, O’Leary

, Brodaty

(2021) Dietary patterns and cognitive health in older adults: Findings from the Sydney Memory and Ageing Study. J Nutr Health Aging25, 255–262.

142.

Limongi

, Siviero

, Bozanic

, Noale

, Veronese

, Maggi

(2020) The effect of adherence to the Mediterranean diet on late-life cognitive disorders: A systematic review. J Am Med Dir Assoc21, 1402–1409.

143.

Kheirouri

, Alizadeh

(2022) MIND diet and cognitive performance in older adults: A systematic review. Crit Rev Food Sci Nutr62, 8059–8077.

144.

Coelho-Júnior

, Trichopoulou

, Panza

(2021) Cross-sectional and longitudinal associations between adherence to Mediterranean diet with physical performance and cognitive function in older adults: A systematic review and meta-analysis. Ageing Res Rev70, 101395.

145.

Buckinx

, Aubertin-Leheudre

(2021) Nutrition to prevent or treat cognitive impairment in older adults: A GRADE recommendation. J Prev Alzheimers Dis8, 110–116.

146.

Rodrigues

, Asamane

, Magalhães

, Sousa

, Thompson

, Santos

(2020) The association of dietary patterns with cognition through the lens of neuroimaging-a Systematic review. Ageing Res Rev63, 101145.

147.

Neth

, Mintz

, Whitlow

, Jung

, Solingapuram Sai

, Register

, Kellar

, Lockhart

, Hoscheidt

, Maldjian

, Heslegrave

, Blennow

, Cunnane

, Castellano

, Zetterberg

, Craft

(2020) Modified ketogenic diet is associated with improved cerebrospinal fluid biomarker profile, cerebral perfusion, and cerebral ketone body uptake in older adults at risk for Alzheimer’s disease: A pilot study. Neurobiol Aging86, 54–63.

148.

Brinkley

, Leng

, Register

, Neth

, Zetterberg

, Blennow

, Craft

(2022) Changes in adiposity and cerebrospinal fluid biomarkers following a modified Mediterranean ketogenic diet in older adults at risk for Alzheimer’s disease. Front Neurosci16, 906539.

149.

Lilamand

, Mouton-Liger

, Paquet

(2021) Ketogenic diet therapy in Alzheimer’s disease: An updated review. Curr Opin Clin Nutr Metab Care24, 372–378.

150.

Grammatikopoulou

, Goulis

, Gkiouras

, Theodoridis

, Gkouskou

, Evangeliou

, Dardiotis

, Bogdanos

(2020) To keto or not to keto? A systematic review of randomized controlled trials assessing the effects of ketogenic therapy on Alzheimer disease. Adv Nutr11, 1583–1602.

151.

Pavón

, Lázaro

, Martínez

, Amayra

, López-Paz

, Caballero

, Al-Rashaida

, Luna

, García

, Pérez

, Berrocoso

, Rodríguez

, Pérez-Núñez

(2021) Ketogenic diet and cognition in neurological diseases: A systematic review. Nutr Rev79, 802–813.

152.

Phillips

MCL

, Deprez

, Mortimer

GMN

, Murtagh

DKJ

, McCoy

, Mylchreest

, Gilbertson

, Clark

, Simpson

, McManus

, Oh

, Yadavaraj

, King

, Pillai

, Romero-Ferrando

, Brinkhuis

, Copeland

, Samad

, Liao

, Schepel

JAC

(2021) Randomized crossover trial of a modified ketogenic diet in Alzheimer’s disease. Alzheimers Res Ther13, 51.

153.

Ahmad

, Khan

, Ali

, Jo

, Park

, Ikram

, Kim

(2021) Fisetin rescues the mice brains against D-galactose-induced oxidative stress, neuroinflammation and memory impairment. Front Pharmacol12, 612078.

154.

Sharma

, Padwad

(2019) In search of nutritional anti-aging targets: TOR inhibitors, SASP modulators, and BCL-2 family suppressors. Nutrition65, 33–38.

155.

Dima

, Assadpour

, Dima

, Jafari

(2020) Bioavailability of nutraceuticals: Role of the food matrix, processing conditions, the gastrointestinal tract, and nanodelivery systems. Compr Rev Food Sci Food Saf19, 954–994.

156.

Di Lorenzo

, Colombo

, Biella

, Stockley

, Restani

(2021) Polyphenols and human health: The role of bioavailability. Nutrients13, 273.

157.

Wróbel-Biedrawa

, Grabowska

, Galanty

, Sobolewska

, Podolak

(2022) A flavonoid on the brain: Quercetin as aotential therapeutic agent in central nervous system disorders. Life (Basel)12, 591.

158.

Berman

, Motechin

, Wiesenfeld

, Holz

(2017) The therapeutic potential of resveratrol: A review of clinical trials. NPJ Precis Oncol1, 35.

159.

Smith

, Giunta

, Bickford

, Fountain

, Tan

, Shytle

(2010) Nanolipidic particles improve the bioavailability and α-secretase inducing ability of epigallocatechin-3-gallate (EGCG) for the treatment of Alzheimer’s disease. Int J Pharm389, 207–212.

160.

Ishisaka

, Ichikawa

, Sakakibara

, Piskula

, Nakamura

, Kato

, Ito

, Miyamoto

, Tsuji

, Kawai

, Terao

(2011) Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats. Free Radic Biol Med51, 1329–1336.

161.

Rishitha

, Muthuraman

(2018) Therapeutic evaluation of solid lipid nanoparticle of quercetin in pentylenetetrazole induced cognitive impairment of zebrafish. Life Sci199, 80–87.

162.

Moreno

, Puerta

, Suárez-Santiago

, Santos-Magalhães

, Ramirez

, Irache

(2017) Effect of the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer’s disease. Int J Pharm517, 50–57.

163.

Oliveira

, Pinho

, Sarmento

, Dias

ACP

(2022) Quercetin-biapigenin nanoparticles are effective to penetrate the blood–brain barrier. Drug Deliv Transl Res12, 267–281.

164.

Fonseca-Santos

, Chorilli

(2020) The uses of resveratrol for neurological diseases treatment and insights for nanotechnology based-drug delivery systems. Int J Pharm589, 119832.

165.

Katila

, Duwa

, Bhurtel

, Khanal

, Maharjan

, Jeong

J-H

, Lee

, Choi

D-Y

, Yook

(2022) Enhancement of blood–brain barrier penetration and the neuroprotective effect of resveratrol. J Control Release346, 1–19.

166.

Tsai

Y-M

, Chien

C-F

, Lin

L-C

, Tsai

T-H

(2011) Curcumin and its nano-formulation: The kinetics of tissue distribution and blood–brain barrier penetration. Int J Pharm416, 331–338.

167.

Johnson

, Nihal

, Siddiqui

, Scarlett

, Bailey

, Mukhtar

, Ahmad

(2011) Enhancing the bioavailability of resveratrol by combining it with piperine. Mol Nutr Food Res55, 1169–1176.

168.

Cano

, Ettcheto

, Chang

J-H

, Barroso

, Espina

, Kühne

, Barenys

, Auladell

, Folch

, Souto

, Camins

, Turowski

, García

(2019) Dual-drug loaded nanoparticles of Epigallocatechin-3-gallate (EGCG)/Ascorbic acid enhance therapeutic efficacy of EGCG in a APPswe/PS1dE9 Alzheimer’s disease mice model. J Control Release301, 62–75.

169.

Bohn

(2014) Dietary factors affecting polyphenol bioavailability. Nutr Rev72, 429–452.

170.

Kamiloglu

, Tomas

, Ozdal

, Capanoglu

(2021) Effect of food matrix on the content and bioavailability of flavonoids. Trends Food Sci Tech117, 15–33.

171.

Walle

(2011) Bioavailability of resveratrol. Ann N Y Acad Sci1215, 9–15.

172.

Ros

, Carrascosa

(2020) Current nutritional and pharmacological anti-aging interventions. Biochim Biophys Acta Mol Basis Dis1866, 165612.

173.

Huffman

, Justice

, Stout

, Kirkland

, Barzilai

, Austad

(2016) Evaluating health span in preclinical models of aging and disease: Guidelines, challenges, and opportunities for geroscience. J Gerontol A Biol Sci Med Sci71, 1395–1406.

174.

Sikora

, Bielak-Zmijewska

, Dudkowska

, Krzystyniak

, Mosieniak

, Wesierska

, Wlodarczyk

(2021) Cellular senescence in brain aging. Front Aging Neurosci13, 646924.

175.

Johnson

, Fox

, Sperling

, Klunk

(2012) Brain imaging in Alzheimer disease. Cold Spring Harb Perspect Med2, a006213.

176.

Zetterberg

, Blennow

(2020) Blood biomarkers: Democratizing Alzheimer’s diagnostics. Neuron106, 881–883.

177.

Tchkonia

, Palmer

, Kirkland

(2021) New horizons: Novel approaches to enhance healthspan through targeting cellular senescence and related aging mechanisms. J Clin Endocrinol Metab106, e1481–e1487.

178.

Hajjar

, Cafiero

, Hanlon

(2007) Polypharmacy in elderly patients. Am J Geriatr Pharmacother5, 345–351.

179.

Hoel

, Giddings Connolly

, Takahashi

(2021) Polypharmacy management in older patients. Mayo Clin Proc96, 242–256.

180.

Maduro

, Luís

, Soares

(2021) Ageing, cellular senescence and the impact of diet: An overview. Porto Biomed J6, e120.

181.

van den Brink

, Brouwer-Brolsma

, Berendsen

AAM

, van de Rest

(2019) The Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets are associated with less cognitive decline and a lower risk of Alzheimer’s disease-a review. Adv Nutr10, 1040–1065.

182.

Gardener

, Rainey-Smith

(2021) Chapter 48 - The dietary approaches to stop hypertension (DASH) and Mediterranean-DASH intervention for neurodegenerative delay (MIND) diets and brain aging. In Factors Affecting Neurological Aging. Martin CR, Preedy VR, Rajendram R, eds. Academic Press, pp. 553–565.

183.

Lamport

, Williams

(2021) Polyphenols and cognition in humans: An overview of current evidence from recent systematic reviews and meta-analyses. Brain Plast6, 139–153.

184.

Amaya-Montoya

, Pérez-Londoño

, Guatibonza-García

, Vargas-Villanueva

, Mendivil

(2020) Cellular senescence as a therapeutic target for age-related diseases: A review. Adv Ther37, 1407–1424.

185.

Omidifar

, Moghadami

, Mousavi

, Hashemi

, Gholami

, Shokripour

, Sohrabi

(2021) Trends in natural nutrients for oxidative stress and cell senescence. Oxid Med Cell Longev2021, 7501424.

186.

Ito

, Corrigan

, Romero

, Anziano

, Neville

, Stephenson

, Lalonde

(2013) Understanding placebo responses in Alzheimer’s disease clinical trials from the literature meta-data and CAMD database. J Alzheimers Dis37, 173–183.

187.

Olsson

, Lautner

, Andreasson

, Öhrfelt

, Portelius

, Bjerke

, Hölttä

, Rosén

, Olsson

, Strobel

, Wu

, Dakin

, Petzold

, Blennow

, Zetterberg

(2016) CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: A systematic review and meta-analysis. Lancet Neurol15, 673–684.

188.

Blennow

, Hampel

(2003) CSF markers for incipient Alzheimer’s disease. Lancet Neurol2, 605–613.

189.

Jensen

DEA

, Leoni

, Klein-Flügge

, Ebmeier

, Suri

(2021) Associations of dietary markers with brain volume and connectivity: A systematic review of MRI studies. Ageing Res Rev70, 101360.

190.

Staubo

, Aakre

, Vemuri

, Syrjanen

, Mielke

, Geda

, Kremers

, Machulda

, Knopman

, Petersen

, Jack

, Jr. , Roberts

(2017) Mediterranean diet, micronutrients and macronutrients, and MRI measures of cortical thickness. Alzheimers Dement13, 168–177.

191.

Kaur

, Macip

, Stover

(2020) An appraisal on the value of using nutraceutical based senolytics and senostatics in aging. Front Cell Dev Biol8, 218.