Exercise to Mitigate Cerebrovascular Aging: A Geroscience Perspective

Abstract

Aging is characterized by a progressive loss of cellular functions that increase the risk of developing chronic diseases, vascular dysfunction, and neurodegenerative conditions. The field of geroscience has identified cellular and molecular hallmarks of aging that may serve as targets for future interventions to reduce the risk of age-related disease and disability. These hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Several studies show that exercise may favorably affect these processes and thereby have antiaging properties. The primary mechanisms through which exercise confers protective benefits in the brain are still incompletely understood. To better understand these effects and leverage them to help promote brain health, we present current findings supporting the notion that adaptive responses to exercise play a pivotal role in mitigating the hallmarks of aging and their effects on the aging cerebrovasculature, and ultimately contribute to the maintenance of brain function across the healthspan.

Aging entails dynamic cellular and molecular changes that result in loss of function across multiple organ systems, including the brain (1). In the brain, aging is associated with an increased risk of neurodegenerative pathologies such as Alzheimer’s disease (AD) (2) and related cognitive disorders (3). To better understand the fundamental mechanisms of aging that may lead to disease, Lopez-Otin and colleagues identified 12 “Hallmarks of Aging” (1) including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis.

The introduction of this framework provided a systematic perspective on the biological complexity of aging, which allowed for the identification of key processes and facilitated the development of targeted interventions to reduce or reverse specific effects of cellular aging. But perhaps most importantly, the framework integrated various levels of aging, from molecular to cellular to systemic, offering a comprehensive view of how different aspects of aging interact with each other. Building upon the concept of geroscience, which proposes that these “hallmarks of aging” increase a person’s vulnerability to age-related disease, here we provide a review of how these age-related biological changes interact with each other, disrupt normal cerebrovascular mechanisms, and may ultimately lead to cognitive decline. Moreover, we present a novel interpretation highlighting the role of exercise as a key modulator of biological and cerebrovascular aging, and, in turn, cognitive aging. In this review, we present current knowledge while also highlighting the critical gaps in research regarding the influence of exercise on the intricate processes of cerebrovascular aging. By leveraging the fundamental biological and physiological mechanisms underlying cerebrovascular disease and cognitive decline, our goals are to suggest new opportunities for future translational geroscience research, and pave the way for more efficacious, personalized exercise interventions that effectively preserve and enhance cognitive function with aging.

Lifestyle variables may influence the hallmarks of aging and their effects on brain function. Modifiable cardiovascular risk factors such as obesity, diabetes, and hypertension can exacerbate cellular aging leading to earlier and more pronounced vascular diseases, neuropathologies, and cognitive decline (4). Conversely, countermeasures such as a commitment to a healthful diet, maintaining optimal blood glucose and blood pressure levels, avoidance of excess adiposity, and engagement in regular exercise, are widely recommended approaches to ward off cerebrovascular abnormalities and their harmful consequences on brain function (5). Although adherence to any of the healthful lifestyle behaviors contributes to the maintenance of vascular and cerebrovascular health, exercise and its clinical correlate, cardiorespiratory fitness (CRF), are crucial contributors. However, despite the highly recognized benefits of exercise, the underlying mechanisms through which these benefits translate to cognitive resilience in aging remain elusive. In this review, we propose that exercise plays a major role in the vital connection between the hallmarks of aging, the cerebrovasculature, and maintenance of cognitive function (Table 1; Figure 1). Under this framework, the effects of exercise in promoting CRF and mitigating molecular and cellular aging (87,88) provide a compelling argument for its prevailing role in preserving brain function in aging (89).

Table 1.

The Role of Exercise in Mitigating the Cellular Effects of Aging

Hallmarks of Aging	Cellular Hallmarks of Aging	Effects	Exercise Effects
Genomic instability	↑DNA damage (6) ↑DNA mutations (6,7) ↑Apoptosis (8) ↑Senescence (9,10) ↑P53 (9,10)	↑Failure of BBB (11) ↑Waste product buildup (12–14) ↑Hypoperfusion (15) ↑Neuronal damage (15)	↓ROS (16) ↑VEGF (17,18) ↑DNA repair (19,20) ↓Methylation (21) ↓Genomic instability (22)
Telomeres	↑Shortening (23)	↑Genomic instability (23) ↑Cellular senescence (23)	↑Telomerase (24) ↑Clusterin (25) ↓SASP (26) ↓Telomere Shortening (27)
Epigenetic alterations	↓DNA methylation (28) ↑Dysregulated histone modification (29)	↑Senescence (30) ↑Inflammation (30) ↑Atherosclerosis (28) ↑Vascular diseases (28)	↑Methylation (31) ↑Nrf2 (32) ↑SIRT1 (33) ↓Inflammatory cytokines (34). ↑SOD (35,36)
Loss of proteostasis	↑Misfolded proteins (37)	↓Endothelial function (38) ↓Glymphatic clearance (39)	↓Misfolded proteins (40) ↓Protein aggregation (41) ↑Proteosome activity (42) ↑Glymphatic clearance (41)
Nutrient sensing	↓AMPK (43) ↓Sirtuins (43) ↓IGF-1 (43)	↑Cellular metabolic dysfunction (44) ↑Endothelial dysfunction (45)	↑AMPK (46) ↑IGF-1 (47) ↑Sirtuins (48) ↑NAD+ (49) ↑PGC-1α (50) ↑Vascular function (51,52)
Mitochondrial dysfunction	↓Autophagy/mitophagy (53) ↑ROS (53) ↑Inflammatory cytokines (53,54)	↑Endothelial dysfunction (55,56) ↓Cellular function (54,57)	↔mTOR (58) ↑Autophagy/ Mitophagy (59) ↑p53 (60) ↑Mitochondrial biogenesis (61) ↑Mitochondrial DNA repair (60) ↑Vascular function (59) ↑Capillary density (59)
Cellular senescence	↑SASPs (62) ↓NO (63)	↓Endothelial function (64) ↑Failure of BBB (65) ↑Neuroinflammation (66) ↓Waste product removal (67) ↓Neuronal function (63)	↑P16 (68) ↑NO (69) ↔p53 (68) ↓ROS (68)
Stem cell exhaustion	↓Stem cell activity (70)	↑Vascular disease (71) ↓Cerebral blood flow (72)	↑Endothelial progenitor cells (73) ↑SDF-1 (74) ↑NO (75) ↑P13K/AKT (76,77)
Cellular communication	↓Endocrine signaling (78) ↓Neuronal signaling (78)	↑Immune cell malfunction (70) ↑Inflammation (70) ↑Waste products (79,80)	↓Vascular inflammation (81) ↑Myokine IL-6 (82) ↑IL-10 (83,84) ↑IL-1 (83,85) ↓TNF-α (83,86)

Notes: AMPK = adenosine monophosphate kinase; IGF-1 = insulin like growth factor-1; IL = interleukins 10, 6, 1; mTOR = mammalian target of rapamycin; NAD+ = nicotinamide adenine dicleotide; NO = nitric oxide; Nrf2 = nuclear factor erythroid-2-related factor 2; P13k/AKT = phosphoinositide 3-kinases/protein kinase; p53 = protein 53;p16 = tumor suppressor protein; PGC-1 = peroxisome proliferator-activated receptor gamma coactivator1-α; ROS = reactive oxygen species; SASP = senescence associated secretory phenotype; SDF-1 = stromal cell-derived factor-1; SIRT1 = Sirtuin-1; SOD = superoxide dismutase; TNF-α = tumor necrosis factor; VEGF = vascular endothelial growth factor.

Figure 1.

Aging and cardiovascular risk factors interact and affect the hallmarks of aging, which have downstream effects on vascular function. The consequential loss of cerebrovascular integrity leads to neurodegenerative changes and cognitive impairment. Exercise inhibits the cellular effects of aging and mitigates cardiovascular risk factors, resulting in maintenance of brain health and cognition across the healthspan.

Importantly, although many of the benefits of exercise can be explained through the lens of molecular and cellular aging, it is important to clarify that it is unlikely that these changes mediate the totality of the exercise–cerebrovascular risk relationship, especially when considering the direct and acute physiological effects of exercise on cardiac output and cerebral blood flow (CBF). Clarifying these intricate relationships may lead to more effective strategies to promote maintenance of brain health and cognition in aging, potentially reducing the prevalence and impact of neurodegenerative diseases.

Although we fully acknowledge that a discussion encompassing all 12 hallmarks offers a more comprehensive perspective on the aging process, the thrust of our discussion focuses on those that affect cerebrovasculature and cognitive health and may be directly influenced by exercise. We begin our narrative review with a discussion of the cerebrovasculature, hemodynamics, and how they are affected in aging, followed by brief discussions of the hallmarks of aging that affect the brain. For each hallmark, we present evidence for the protective role of exercise on the fundamental mechanisms of aging and how these effects may translate into the maintenance of cerebrovascular health and cognitive function in advanced age.

Search Method

We conducted a comprehensive search of relevant literature across various academic databases such as PubMed, Scopus, and Google Scholar using a combination of relevant keywords and advanced search filters (hallmarks of aging and relevant terms; aging; vascular; cerebrovascular; geroscience; exercise; physical activity). These terms were combined using the Boolean operator “AND” with terms specific to hallmarks of aging such as “genomic instability,” “p53,” “autophagy,” AND “vascular,” “brain” and “exercise.” In addition, we scanned reference lists from relevant manuscripts to identify additional studies.

The Cerebrovasculature, Hemodynamics, and Aging

Although the brain constitutes 2% of body weight, this highly metabolic organ (90) receives 15% of the cardiac output and 20% of the available systemic oxygen via an intricate vascular network that spans more than 400 miles (91). Due to the critical link between the brain’s high metabolic demands and its requirement for a continuous blood supply (90), brain metabolism and CBF are tightly linked and can be influenced by fluctuations in arterial blood pressure, intracranial pressure, and systemic CO₂ and O₂ levels (91).

To satisfy its critical need for CBF, the brain is endowed with an autoregulatory system that maintains a relatively constant blood flow over a wide physiologic range of perfusion pressures. Although the exact determinants of cerebral autoregulation are not yet fully understood, vasoactive agents, such as nitric oxide (NO), H⁺, K⁺, and adenosine, are released when CBF falls and elicits dilation of vessels (91). In the absence of neurodegenerative disease, brain energy metabolism and neuronal activity are directly coordinated such that cerebral activation is consistently followed within seconds by dilation of blood vessels and an increase in CBF (92). The relationship between task-dependent neural activation and the corresponding increase in CBF, termed neurovascular coupling (NVC) (93), is a fundamental physiological process that ensures an adequate blood supply to metabolically active regions of the brain.

With aging, however, cellular and molecular alterations in the brain’s blood vessels result in loss of structural integrity and compromised cerebral hemodynamics, leading to ischemic neuronal damage and associated cognitive dysfunction (94). For example, microvascular changes predispose the cerebral circulation to hypoperfusion (95,96), precipitating the breakdown of the blood–brain barrier (BBB), neuroinflammation, cerebral microhemorrhages, impairments in CBF regulation, and ultimately neurodegeneration and cognitive impairments (94). Similarly, disruptions in NVC can lead to a mismatch between neuronal activity and blood supply, triggering ischemic damage, neuronal dysfunction, cognitive decline, and various neurological disorders (93). Other factors such as systemic and cerebral buildup of lipids and atherosclerotic plaques (97), thickening and stiffening of arterial walls, and loss of pericytes that surround the cerebral capillaries (98) precipitate further endothelial dysfunction (95,99). A key feature of the ensuing endothelial dysfunction is the marked decrease in the production of the vasodilator NO and an increase in the vasoconstrictor endothelin-1 (100,101), which can impair CBF regulation and potentially contribute to the development of neurovascular disorders (102).

Moreover, age-related elevations in arterial blood pressure can have direct effects on CBF. In people with impaired cerebral autoregulation, which may occur in the presence of untreated hypertension, as blood pressure increases, blood flow to the brain may also increase (91), raising the risk of cerebral hyperperfusion. Consequently, to protect the brain from the detrimental effects of hyperperfusion, cerebral vessels vasoconstrict, thus initiating compensatory reductions in CBF (91). However, with long-term hypertension management, as shown in the SPRINT MIND trial (103), improvements in cerebral autoregulatory capacity and carotid distensibility were possible, potentially leading to increased CBF (103). Our earlier findings support the notion that the management of blood pressure in older adults with hypertension can have beneficial outcomes on both CBF and carotid distensibility, suggesting a restoration of autoregulatory efficiency with appropriate treatment (104). Conversely, reductions in CBF due to orthostatic hypotension, postprandial hypotension, or other daily hypotensive events can precipitate ischemic damage to watershed regions of the brain, resulting in ischemic injury, and neuroinflammation. In support of this notion, animal and human studies show that a decrease in perfusion is associated with the accumulation of white matter lesions (105) in the deep watershed zones of the brain, which significantly increase the risk of dementia and age-related cognitive impairment (102).

Loss of arterial elasticity is another significant age-related vascular change. Vascular stiffness, particularly in the aorta, increases flow pulsatility to high-perfusion organs, such as the brain. The increase in pulsatility results in cerebral microvascular damage and subsequent cognitive decline in older adults (106). Additionally, arterial stiffness can impair the brain’s autoregulatory mechanism leaving the brain vulnerable to extremes in perfusion pressures, contributing to cognitive decline (107). Furthermore, arterial stiffness increases cardiac left ventricular afterload. This increase causes myocardial stiffening, left ventricular hypertrophy, and decreased diastolic ventricular filling, thereby decreasing cardiac output (Q), particularly during preload reduction (108). Due to the dependence of the brain on cardiac blood supply, reductions in Q can compromise cerebral white matter integrity (109–111) and have been shown to disrupt proteostasis, leading to an abnormal buildup of cellular waste products such as amyloid beta (Aβ), hyperphosphorylated tau (p-tau), and neurofibrillary tangles in the brain (12–14). Although the exact mechanisms underlying neurodegeneration and cognitive decline in AD have yet to be fully defined, recent attempts identified the role of activated microglia (112) and neuroinflammation (113) in the pathogenesis of the disease. Promising evidence indicates that alterations in the cerebrovasculature may be mitigated by physical exercise, which has been associated with enhanced endothelial function and vascular health (88,114,115).

Hallmarks of Aging, Their Impact on the Cerebrovasculature, and the Effects of Exercise

The fundamental mechanisms of biological aging (116) are not distinct processes, but interact to affect cellular function (94). For instance, genomic instability, telomere attrition, epigenetic changes, and loss of proteostasis are incontrovertibly harmful cellular events associated with aging and are therefore considered primary “hallmarks” of aging. Disruptions in nutrient sensing, mitochondrial functions, and cellular senescence are termed antagonistic hallmarks because they initially compensate or counteract the damage induced by the primary hallmarks, but under chronic conditions, become harmful over time. Lastly, integrative hallmarks such as stem cell depletion and disrupted cell-to-cell communication, which manifest after irreparable damage from the primary and antagonistic hallmarks, can impair a cell’s repair capacity and cause further cellular degeneration (1,23,38,62,71,116–120).

Genomic Instability

Genomic instability refers to damage in the DNA sequence of a cell, which may be isolated to certain regions of the genome or may involve the entire genome (6). DNA damage can manifest as a result of mutations, replication errors, deletions or rearrangements (6), telomere shortening (121), and disruptions in tissues and organs including endothelial and vascular functions (122).

DNA damage impairs molecular integrity and alters protein coding, giving rise to mutations that promote aging. For instance, oxidative damage may transform DNA into a DNA adduct (8-OHdG) with a high mutagenic potential, resulting in DNA mutations and instability (7). Similarly, DNA instability occurs as a consequence of defects in DNA repair mechanisms and leads to increased rates of DNA mutations (121). With increased instability, the replicative phenotype shifts to a survival protective mechanism that includes apoptosis and cellular senescence (8). If DNA repair is initiated, tumor protein 53 (p53), a transcription factor that plays critical roles in cell growth, DNA repair, and apoptosis, can become overexpressed and induce cellular senescence to protect against further genomic instability (9,10). In the setting of the brain, senescent cells can lead to dysfunction of the neurovasculature and failure of the BBB (11), potentially inducing hypoperfusion, increased permeability, and subsequent neuronal damage (Table 1; Figure 1) (15).

Effect of Exercise on Genomic Instability

Moderate-intensity exercise serves an important role in the maintenance of cellular health and function, contributing to genomic stability as demonstrated by a study in healthy men between 40 and 74 years of age (19). Compared to the control group, following 16 weeks of combined aerobic and resistance training, DNA strand breaks and oxidative DNA damage decreased, while a nonstatistical increase in DNA repair capacity was observed in plasma lymphocytes in the exercise group (mean age = 58.4 ± 10.2) (19). The beneficial impact of exercise on DNA integrity is reinforced by research indicating that an exercise-induced increase in reactive oxygen species (ROS) elicits an upsurge in the levels of antioxidant enzymes, both in human skeletal muscle (123) and in plasma (124). These findings are supported by basic and human research showing exercise-induced upregulation of antioxidant enzymatic genes associated with defense against ROS (16,124,125) and DNA repair (20). Exercise has also been shown to promote regulation of DNA methylation in human skeletal muscle (21), support endothelial function (114), and mitigate genomic chromosomal damage in older adults (22). However, the effects of exercise on these mechanisms in the human brain have not been thoroughly investigated.

Central to the beneficial effects of exercise on genomic stability is the indirect but nevertheless critical role of vascular endothelial growth factor (VEGF), which is reduced in aging skeletal muscles where VEGF mRNA and protein levels, and capillarization have been shown to decrease in men (126) and women (127). Controlled animal studies (128) and vitro research (129) show that exercise-induced VEGF and angiogenesis improve skeletal muscle (130) and cerebral vascular density (131) and cerebral blood supply (128). In turn, the improvement in blood flow may contribute to genomic stability by reducing DNA damage that occurs from hypoxia and oxidative stress (129).

In humans, exercise training has been shown to increase VEGF in serum (17) and plasma (18), whereas other studies reported no effect of exercise training on VEGF in older adults (132). The discrepancies between positive and negative findings may be attributed to different exercise modalities (aerobic vs resistance), exercise intensity, and the heterogeneity of participant selection (132), highlighting the need for more research.

Although the question of whether systemic VEGF can cross the BBB remains an unresolved area of investigation, evidence from animal research reported exercise-induced elevations in hippocampal VEGF (133,134), suggesting VEGF penetration into the brain. However, evidence in the human brain is still emerging, with limited indications of an increase in VEGF in cerebrospinal fluid after exercise. Yang et al. (135) explored the impact of acute moderate-intensity upper body resistance training on VEGF in the cerebrospinal fluid (CSF) of older patients with normal-pressure hydrocephalus. Lumbar CSF was collected 1 and 2 hours before exercise, and at 3 hourly time points after exercise. Compared to the control group, a significant increase in CSF-VEGF was observed only in the exercise group (135).

Considering the evidence suggesting a possible link between exercise-induced VEGF, angiogenesis, and genomic stability in the human brain, the lack of a definitive link highlights the need for further research to uncover how a stable and responsive peripheral circulatory system, fortified against genomic instability via exercise-induced VEGF, may contribute to the preservation of cerebral vascular health. During aging when VEGF levels are known to decrease (126), increasing VEGF through exercise may be particularly beneficial.

Telomere Shortening

Telomeres are protective chromosomal endcaps whose primary function is to defend chromosomes against genomic instability during cell division. As such, telomeres, which do not fully replicate during mitotic division, gradually shorten with aging. Following repeated cell divisions, telomeres reach a critical length, lose their protective functions, and ultimately initiate cellular senescence (23). Dysfunctional telomeres may reflect overall cellular aging and may serve as biomarkers for an increased risk of developing vascular dementia (VaD). One study reported that older adults diagnosed with VaD exhibited shorter telomeres compared to adults with cerebrovascular or cardiovascular diseases without cognitive decline, adults with AD, and healthy controls. These results suggested a link between telomere length and vascular dementia, independent of other factors (136). A subsequent study, which did not include a control group, reported no differences in telomere length between adults with late-onset AD and VaD (137).

Exercise Effects on Telomere Shortening

Telomerase is an enzymatic protein that resists cellular aging by countering telomeric shortening. However, during embryonic development, the human catalytic subunit of telomerase (hTERT) becomes inactivated in most somatic cells, limiting cell division resulting in undetectable telomerase expression (138,139). Nevertheless, in healthy adults, telomerase may still be active in cells that have a high mitotic potential, such as germline cells, and self-renewing cells, such as peripheral blood mononuclear cells (138).

Evidence shows that chronic exercise can counteract telomere shortening via an increase in telomerase in human mononuclear cells and may thereby have a protective role in systemic vascular aging (24,27,140,141). Other studies reported negative correlations between leukocyte telomere length and cardiovascular and cerebrovascular diseases such as ischemic stroke (142,143), suggesting that maintaining telomere length with physical activity may benefit the vascular system, with possible implications for cerebrovascular health.

Elevations in telomerase activity in trained athletes may impact other systemic cellular aging processes. Protection against telomere shortening preserves genomic stability (23,27), which may moderate endothelial cellular aging and senescence, and reduce concentrations of pro-inflammatory cytokines, collectively referred to as senescent-associated secretory phenotypes (SASPs) (26), that further contribute to telomere shortening (144).

Another factor that may play a role in the relationship between exercise, telomere shortening, and brain health is the exercise-induced extracellular chaperone protein, clusterin (CLU). CLU, which is elevated in older adults with AD and mild cognitive impairment (MCI) (25), is associated with reductions in brain inflammation and is emerging as a critical player in mitigating cellular stress and the inflammatory response (25,145). Although indirect, CLU’s role in protecting cells against inflammation may provide a significant buffer against the cascade of cellular aging and telomere erosion, which may have cerebral vascular benefits. In support of this, researchers examined key plasma proteins before and after 6 months of training in 20y adults (mean age = 69.68 ± 7.95) with amnestic MCI (146). The exercise program consisted of 3 weekly sessions of combined aerobic and resistance training. Although there was no control group, compared to baseline values, CLU increased (146). Given the anti-inflammatory effects of CLU, an exercise-induced increase in CLU may benefit the brain if it prevents the adverse effects of systemic inflammation on BBB dysfunction (147) and neurodegeneration (148). In summary, the presented studies suggest that exercise may protect against neuronal aging via beneficial effects on telomerase activity, telomere length, and inflammation.

Epigenetic Alterations

Epigenetic alterations, including histone modifications and abnormal DNA methylation, alter gene expression without altering the underlying DNA sequence, and can occur following exposure to environmental factors and lifestyle behaviors (149). Disruptions in blood flow within the vascular walls, for instance, have been shown to increase DNA methyltransferase, which initiates broad changes in DNA methylation that can affect gene activity and impair DNA repair capacity (28). These changes, along with histone modifications (29), can lead to DNA double-strand breaks, which can indirectly induce genomic damage (118) and ultimately affect the pathogenesis of AD (150). For instance, DNA methylation may silence genes responsible for the clearance of waste products (150) thereby contributing to disruptions in proteostasis. In turn, a breakdown of proteostasis alters the function of vascular cells, giving rise to endothelial cell senescence, vascular remodeling, atherosclerosis, and inflammation (Table 1; Figure 1) (30,151).

Exercise Effects on Epigenetic Alterations

Exercise results in alterations of DNA methylation profiles and histone modifications (31), which have systemic effects and potential implications for the cerebral vasculature. Albeit indirect, collective evidence from exercise studies suggests a linkage between exercise-induced epigenetic changes, antioxidant expression, and cerebral vasculature.

ROS are recognized stimulants for transcription of genes involved in the adaptive response to exercise-induced oxidative stress (32,152). A key element in this antioxidant response to exercise is the “master regulator,” nuclear factor erythroid-2-related factor (Nrf2) (32). Nrf2 is a transcription factor that is deacetylated by sirtuins (33). Sirtuins (mainly, 1, 6, and 7) are highly conserved proteins of NAD+-dependent histone deacetylases that target histones and transcription factors, contributing to epigenetic regulation of cell phenotypes. The interaction between Nrf2 and SIRT1enhances Nrf2 binding to the antioxidant responsive element (ARE), which regulates transcription of various cytoprotective and antioxidant genes (33) such as superoxide dismutase (SOD) (32,152). Once activated, the Nrf2-ARE mechanism enhances cellular energy and redox balance, protects against neurotoxicity (153), and suppresses inflammation by inhibiting IL-6, IL-1β, and IL-17 gene expression (34).

The downstream activation of Nrf2 and its associated protective effects in animals provides a compelling link between systemic physiological adaptations and prevention or mitigation of cerebral vascular and neurological dysfunctions. For instance, Nrf2 appears to improve systemic vascular endothelial dysfunction by inhibiting oxidative stress (154,155), whereas reduced Nrf2 activity is inversely related to several brain conditions including experimental stroke (156,157), brain injury, cerebrovascular, and neurodegenerative models (158). To determine the impact of Nrf2 upregulation in cerebral vessels following ischemic stroke, Alfieri et al. (159) compared 2 groups of rats where 1 group was pretreated with an Nrf2 stimulator prior to middle cerebral artery occlusion and the other was not. Expression of heme oxygenase, an enzyme involved in catabolism of heme that becomes activated during cellular stress and inflammation, increased in the cerebral microvessels surrounding the infarct in the untreated ischemia group. However, pre-activation with an Nrf2 stimulant (sulforaphane, SFN) increased Nrf2 expression in cerebral microvessels and prevented neurological and BBB dysfunction in the pretreated animals (159). In another study, 2 groups of mice (wild-type and Nrf2 knockout) were pretreated with SFN. In the wild-type group, Nrf2 increased and resulted in the upregulation of antioxidant enzymes in the striatum and cortex, with parallel reductions in inflammatory cytokines and gliosis. These effects were not observed in the Nrf2 knockout mice (160). Collectively, these results provide evidence for the role of pharmacologically activated Nrf2 on antioxidant gene expression, and their potential protective effect on cerebral microvessels in animals.

Evidence from exercise studies in animals support the notion that physical activity may exert comparable stimulatory effects on sirtuins and the Nrf2 signaling cascade (32,35). In humans, activation of the Nrf2 pathway in skeletal muscle and blood leads to enhanced expression of SOD genes, with higher responses following HIIT (35,36). However, this response is diminished in sedentary older participants (161). Compared to their sedentary counterparts, active older adults exhibited a higher Nrf2-mediated antioxidant response, suggesting that chronic exercise may mitigate an age-related decline in Nrf2 signaling (162).

Little is known about exercise-induced Nrf2 expression in the brain. However, evidence for Nrf2 changes in hippocampal, cortical, and hypothalamic structures has been reported following vigorous exercise in adult mice (163). The robust activation of Nrf2 in animal studies, particularly within brain tissues, constitutes a potential neuroprotective mechanism elicited by exercise. Whether comparable exercise-induced Nrf2 effects occur in the human brain is unknown. However, the broader implications of Nrf2-signaling for genomic integrity suggest that mechanisms of antioxidant protection with downstream effects on brain blood vessels may be operational in humans. This proposition is strengthened by evidence linking Nrf2 upregulation with neuroprotection and Nrf2 deficiencies with neurodegenerative diseases which are characterized by increased oxidative stress (159,164). To enhance our understanding and potential therapeutics for neurodegeneration, further research in humans is needed to clarify the precise epigenetic pathways through which exercise might improve Nrf2 signaling and its effects on cerebrovascular function and brain health.

Loss of Proteostasis

Proteostasis entails an intricate balance between synthesis, folding, and degradation of proteins. With aging, the capacity of this system to maintain its coordinated functions becomes disrupted and leads to an accumulation of misfolded proteins. In this misfolded state, proteins lose structural integrity and assume a toxic profile that can initiate cellular and tissue damage (37). Examples of misfolded proteins include Aβ, alpha synuclein, prion proteins, and superoxide dismutase which is implicated in apoptosis (165–167). Protein misfolding can damage neuronal and glial cells, leading to cellular dysfunction, neurodegenerative diseases (AD, Parkinson’s, Creutzfeldt–Jakob, Huntington, amyotrophic lateral sclerosis), and cognitive decline (165). In the vascular system, an accumulation of misfolded proteins, such as members of the apolipoprotein family, α-antitrypsin and medin, contribute to endothelial dysfunction, a key factor in the development of systemic and central vascular diseases (38,168), cerebrovascular dysfunction (169), and cognitive impairment (170).

Lastly, the role of the glymphatic system can be considered in the context of loss of proteostasis. The glymphatic system is a newly discovered cerebral waste drainage system in the brain, similar in function to the systemic lymphatic system (171). The glymphatic system is intricately involved in the regulation of interstitial Aβ deposition (41), whose aggregation is implicated in neurodegenerative processes. With aging, the activity of the glymphatic system is reduced, such that cerebral waste clearance is lower in older compared to younger adults (39). The reductions in glymphatic clearance have been associated with a decrease in cerebral gray matter volume and parallel reductions in cognitive function in older adults (Table 1; Figure 1) (172).

Effects of Exercise on Proteostasis

Exercise enhances proteostasis by promoting autophagy (173). For instance, the proteosome activity improved in rats (174), and in older hypertensive adults following aerobic and resistance exercise training (42), while exercise-induced degradation of misfolded proteins was shown in both animal and human muscle (40). Consequently, by stimulating autophagy and removing toxic protein aggregates and damaged organelles in the brain and in blood vessels, exercise aids in the maintenance of neural function and CBF (175). In turn, adequate CBF, not only safeguards the delivery of nutrients to the brain but may also assist in the removal of waste products, including misfolded proteins (41,79,176).

Additionally, emerging evidence indicates that exercise may enhance glymphatic activity (41,177). To illustrate, glymphatic transport is propelled by the pulsatility of the arterial walls and moves in the same direction as blood flow (14) along astrocyte-supported perivascular channels that drive CSF into the brain and interstitial fluid out of the brain along perivenous spaces (14). Given the dependence of the glymphatic system on arterial pulsatility, the clearance of waste products may be partially driven by changes in physical activity (41,177). Ultimately, the interdependence between cardiac output, arterial pulsatility, and the glymphatic system highlights the role of exercise-induced neuroprotection via cerebral waste product removal (176,177). In this way, the glymphatic system plays a part, albeit indirectly, in autophagy and mitochondrial function and in sustaining cellular homeostasis.

Nutrient Sensing

Nutrient-sensing pathways, including adenosine monophosphate kinase (AMPK), mammalian target of rapamycin (mTOR), sirtuins, and IGF-1, are also dysregulated with aging (43). AMPK maintains mitochondrial homeostasis and mitophagy (mitochondrial autophagy), and is promptly activated following energetic stress induced by nutrient deficiency, hypoxia, ischemia, and exercise (51,178). Once activated, AMPK plays a role in endothelial NO synthase (eNOS) production (179) and angiogenesis (51). By contrast, mTOR stimulates anabolic processes under conditions of high nutrient availability, and plays a central role in energy metabolism by integrating energetic and growth factor signaling with cellular processes such as stress resistance and autophagy (180). Given its function as a signaling target for growth factors, mTOR plays a critical function in regulating angiogenesis in endothelial cells (45). Together, AMPK and mTOR serve as modulators of the signaling cascades of IGF-1 involved in glucose sensing, angiogenesis, and capillarization (181).

Sirtuins, silent information regulators (SIRT 1-7), are conserved histone deacetylases that belong to a class of nicotinamide adenine dinucleotide (NAD⁺)-dependent enzymes that play an essential role in regulating cellular responses to nutrient availability (44). Sirtuins influence metabolism by regulating gluconeogenesis and fatty acid oxidation by deacetylating transcription factors (44). Once activated, sirutins deacetylate eNOS leading to increased production of NO in endothelial cells. In addition, sirtuins participate in growth factor regulation and can promote angiogenesis. As such, members of the sirtuin family initiate broad effects that result in enhanced vascular health (48), extended lifespans, and protection from neurodegenerative diseases (44). Interestingly, evidence for expression of SIRT1 in the rodent and human central nervous systems has been reported (182). In animals, the presence of SIRT1 in the small resistance vessels of the brain contributed to cerebral blood vessel dilation, whereas its inhibition decreased dilation of blood vessels (183). Similarly, in a model of cerebral ischemia, SIRT1 preserved CBF and restored cerebrovascular reserve in mice with SIRT1 overexpression compared to a group of wild-type mice (184).

Effects of Exercise on Nutrient-Sensing Pathways

Key nutrient-sensing pathways including IGF-1, NAD⁺, and sirtuins are modulated by resistance (47) and anaerobic exercise (49,185). Exercise-induced release of IGF-1 stimulates ribosomal biogenesis and protein synthesis (50), which have been positively associated with blood vessel density in the brain, CBF, and cognitive function (117,186–189). Similarly, exercise increases NAD⁺ levels, and counteracts the age-related decline in NAD⁺ in both animals and humans (190). The increase in NAD+ activates sirtuins in a wide variety of tissues that influence a broad range of cellular and vascular processes described earlier (44,48). Although human studies to examine the direct role of exercise-induced SIRT1 on cerebral circulation are lacking, evidence from animal studies highlights the role of SIRT on cerebral vasodilation (183), and underscores its potential impact on CBF (184).

Lastly, the AMPK pathway is also activated with moderate-to-heavy exercise intensities (46). The upregulation of AMPK conserves adenosine triphosphate leading to activation of PGC-1α and its downstream effects on mitochondrial biogenesis (50), which is critical to cellular energy production. Moreover, activation of AMPK has protective effects. AMPK inhibits inducible transcription factors involved in inflammatory responses in the vasculature (52), improves vascular function and CBF via NO-dependent vasorelaxation (52), and angiogenesis via an increase in VEGF (51). Therefore, by optimizing nutrient-sensing signaling, exercise may improve the responsiveness of the vascular system to cerebral metabolic demands, and may play a pivotal role in the preservation of vascular and cognitive function in aging (191).

Mitochondrial Dysfunction

Mitochondria are responsible for energy production, intracellular calcium regulation, and their own protein synthesis. With age, however, mitochondrial function and mitophagy (mitochondrial autophagy) activity decline, resulting in impairment in cellular energy production (53,192). Mitophagy, which is instrumental in maintaining cellular homeostasis and promoting cell survival, functions as a protective mechanism that selectively degrades damaged or dysfunctional mitochondria (193). However, when mitophagy is disrupted, failing mitochondria produce high levels of ROS and inflammatory cytokines, which can quickly overwhelm the cell’s antioxidant abilities, leading to inflammation (53) and overall loss of cellular function (54). Furthermore, loss of mitophagy results in decreased energy production, generation of pro-apoptotic factors, and onset of endothelial dysfunction (55). Given these effects, deficits in mitochondrial function are frequently identified as contributors to vascular endothelial dysfunction (53) and neurodegenerative diseases (56,194). Mitochondrial dysfunction has also been implicated in vascular cognitive impairment, MCI, and dementia (Table 1; Figure 1) (195–197).

Effects of Exercise on Mitochondrial Dysfunction

Human studies have shown that exercise initiates widespread changes in muscle mitochondria. Specifically, exercise-induced mechanical shear stress mitigates oxidative damage via the release of PGC-1α (59) whose downstream effects on growth factor cascades enhance muscular mitochondrial and capillary density (61,198). Enhanced mitochondrial and capillary density following chronic endurance exercise improves oxygen delivery, enhances oxidative phosphorylation for energy (adenosine triphosphate; ATP) production, and augments the production of antioxidant enzymes (eg, superoxide dismutase) in muscle (58). Together, these beneficial effects lead to a reduction in ROS and their consequent deleterious effects on vascular function (59,179).

Additionally, physiological adaptations to low- or moderate-intensity exercise regulate the expression of membrane receptor adhesion molecules (199), which amplify mitophagy through the inhibition of mTOR and phosphorylation of AMPK. These coordinated events augment the production and availability of NO and ensure both mitochondrial health and optimal vascular tone (59). Lastly, p53, which takes part in mitochondrial biogenesis and DNA repair, increases in muscle following moderate aerobic exercise (60). Considering the fundamental function of mitochondria in cellular energy production in capillary pericytes that regulate vasodilation and vasoconstriction, the effects of exercise on mitochondrial density may also help to ensure precise regulation of cerebral vessels (200), which is vital for maintaining overall brain health and function.

Cellular Senescence

DNA damage, mitochondrial dysfunction, enhanced ROS production, and telomere attrition are some of the age-related changes that trigger cellular senescence (201). Senescent cells lose their ability to divide but remain metabolically active despite undergoing cell-cycle arrest. In this state, they adopt an immunologic phenotype and begin to secrete interleukins and pro-inflammatory SASPs that promote chronic inflammation (62). Once initiated, cellular senescence negatively affects the proliferation of neural stem cells (202) that give rise to neurons and neuroglia, culminating in a reduction in neurons, oligodendroglia, and astrocytes, which can impair neuronal and synaptic function (203) and result in cognitive decline (63). Indeed, a growing body of evidence links the buildup of senescent cells to neurodegenerative pathologies and dysfunction (204). Reducing senescent cells with treatments known as senolytics (eg, Dasatinib, Quercetin, Rapamycin, Fisetin), which are compounds that help induce senescent cell death, have shown promise in mitigating the effects of cellular senescence in animal (205) and human studies of AD (206).

In endothelial cells, cellular senescence results in decreased production of NO and impaired vasodilation (64), which may compromise the blood flow response to neural activity (93). Furthermore, the accumulation of senescent vascular cells can impair BBB integrity thereby allowing systemic pro-inflammatory cytokines to infiltrate the immune-privileged brain (11,63). The breakdown of the BBB is associated with loss of pericytes and transporter functions, and impaired waste product removal resulting in neuroinflammation and neuronal dysfunction (63,66,67).

Effects of Exercise on Cellular Senescence

Exercise is protective against cellular senescence, especially in vascular endothelial cells, which are critical for preserving vascular function during aging (26,68). This protective effect is facilitated by several mechanisms, including activation of sirtuins, upregulation of telomerase activity, and enhanced NO availability (see discussions earlier). Collectively, these exercise-induced effects affect the expression of tumor suppressor p16^ink4a (p16), a cyclin-dependent kinase inhibitor that plays a pivotal role in cellular senescence including contributing to vascular endothelial dysfunction in sedentary older adults (68). When stimulated by exercise, SIRT1-mediated histone deacetylation can result in a more closed chromatin state at the p16 gene locus, which reduces its transcription and subsequent expression (207). This effect is evident in trained athletes, where studies showed upregulated telomerase activity and downregulated p16 expression in circulating peripheral blood mononuclear cells compared to untrained controls (140). Additionally, compared to baseline levels, 12 weeks of exercise reduced p16 levels and expression of cellular senescence markers in older adults (26), further supporting the systemic influence of exercise on cellular senescence. Moreover, chronic exercise restores NO availability (69), and modulates age-related imbalances in p53 levels in the endothelial cells of peripheral vessels in humans (68), thereby reducing oxidative stress in older athletes and safeguarding systemic vascular health (68).

In the context of cerebral vessels, mitigating cellular senescence preserves endothelial and vascular function (68), BBB integrity, and neuronal and glial activity (208,209), which are key determinants of cerebral autoregulation, CBF, and cognitive function (108,210). Although direct assessment of exercise effects on cellular senescence in the human cerebral vasculature is lacking, the established effects of exercise in the peripheral vascular system suggest similar benefits for the cerebral vessels. This generalization is supported by evidence from converging lines of research including a study that linked the accumulation of p16 and senescent cells to the breakdown of the BBB and neurovascular dysfunction in mice (11), coupled with evidence for elevated p16 levels in postmortem brain slices of adults with AD, which were not present in non-AD-matched controls (211).

Therefore, by regulating the molecular pathways that affect cellular senescence, chronic exercise may contribute to the preservation of cerebral vascular integrity and cognitive function in aging. Although promising, verification in humans is required to assess the impact of exercise on cerebral senescence markers and cerebrovascular health.

Stem Cell Exhaustion

The accumulation of DNA damage, buildup of SASPs, telomere shortening, mitochondrial dysfunction, and epigenetic changes in turn lead to reductions in stem cell activity (70). Stem cell exhaustion has far-reaching consequences on repair mechanisms of the endothelium, the BBB, neurogenesis, and neurovascular function. For instance, in the vascular system, stem cell exhaustion contributes to the formation of atherosclerosis (212), which may lead to reductions in CBF (72), buildup of waste products, and neurovascular dysfunction (79). Similarly, loss of repair activities in the vasculature (71) can limit the regenerative ability of neuronal and BBB cells, making the brain more permeable to pathogens and neuroinflammation. Therefore, the effects of stem cell exhaustion, alone or in combination with other hallmarks of aging, can play a significant part in age-related cognitive decline (203).

Exercise Effects on Stem Cells

Exercise affects a cascade of molecular processes that stimulate stem-cell-mediated vascular repair. These processes include the migration and proliferation of endothelial progenitor cells (EPC) from bone marrow and other tissue reservoirs into the peripheral blood (73), and the upregulation of growth factors in humans (213). The exercise-induced increase in VEGF enhances the proliferation and migration of EPCs (214). In parallel, stromal cell-derived factor-1 (SDF-1) functions as a chemoattractant that helps guide EPCs to vascular injury sites, as demonstrated in damaged murine carotid arteries (74). Moreover, activation of the PI3K/Akt signaling pathway promotes the survival and function of EPCs (76,77), and the upregulation of eNOS. Once activated, NOS contributes further to the mobilization of EPCs and modulation of vascular tone via an increase in NO (75).

Ultimately, these molecular changes are vital for maintaining the integrity of the BBB and ensuring adequate CBF, which is necessary for the delivery of EPCs to areas within the brain that require repair following intracerebral hemorrhage and ischemic stroke. One study of patients with intracerebral hemorrhage observed that increased levels of circulating EPCs were associated with better clinical outcomes, supporting their role in neurovascular repair processes (215). Another study found that EPCs isolated from blood following ischemic stroke in older adults (mean age = 70) were associated with better BBB permeability, which independently predicted better clinical outcomes (216). A direct link between exercise-induced EPC mobilization and enhanced cerebral vascular function in humans remains to be established.

Altered Intercellular Communication

With aging, endocrine, neuroendocrine, and neuronal signaling begins to fail (78). Loss of inhibitory signaling in these systems can lead to chronic release of stress hormones and cytokines, giving rise to immune system malfunction and inflammation (70). The inflammatory consequence of age-related failure of intercellular communication has been termed “inflammaging.” This phenomenon is characterized by an overproduction of pro-inflammatory cytokines (70), and the breakdown of the BBB (147). This inflammatory response is increasingly identified as a significant risk factor for strokes, and onset of cerebral small vessel disease (217). Furthermore, the breakdown of intercellular communication and the resulting inflammation have been identified as contributors to the buildup of Aβ (80,218), in facilitating the propagation of tau pathology between cells (219), and in cognitive decline (220).

Exercise Effects on Intercellular Communication

Exercise plays a critical role in enhancing intercellular communication, mitigating inflammation, and maintaining the health of blood vessels. Evidence from human studies indicates that aerobic, anaerobic, and resistance training modulate inflammatory biomarkers (81,83). For instance, chronic exercise inhibits pro-inflammatory cytokines (221,222) and protects endothelial (223) and vascular functions (88). One way by which exercise confers these benefits is via the release of interleukin-6 (IL-6) from muscle (82). Contrary to the pro-inflammatory IL-6 released by macrophages, IL-6 released from muscle appears to have anti-inflammatory benefits and is present in significantly higher concentrations than macrophage IL-6 (82). The higher concentrations of myokine-produced IL-6 inhibit systemic inflammation (224) by stimulating the release of other anti-inflammatory interleukins such as IL-10 and IL-1 receptor antagonist, which suppress the pro-inflammatory cytokine TNF-α (86,224). Ultimately, the anti-inflammatory effects of exercise protect the vascular BBB (147), aid in the maintenance of neuronal and glial function, and in the preservation of cognitive function with aging (225).

In summary, the underlying mechanisms of age-related vascular disorders are highly complex, encompassing a wide array of interactions and pathological consequences that give rise to cerebrovascular dysfunction. However, chronic exercise may mitigate the effects of cellular aging (Table 1), and has been shown to be associated with better vascular health, maintenance of brain function in aging (4,81,114,115,226), and decreased mortality risk (227).

Exercise, Cerebral Hemodynamics, and Cognitive Function

As noted earlier, exercise effects on vascular endothelial function underlie some of its benefits on cerebral hemodynamics and cognition (115). This notion is supported by evidence from a large meta-analysis of 51 randomized controlled trials of 2 260 middle-aged and older adults that reported improvements in endothelial function with exercise (228). Moreover, lifelong exercisers who maintained higher CRF into older age had higher CBF and cerebrovascular reactivity (CVR) compared to their sedentary counterparts (96,226). However, even shorter duration exercise training (12 weeks) can improve cerebral hemodynamics (229), and cerebral blood volume (CBV) in the dentate gyrus in healthy older adults (230). Interestingly, a parallel animal study by the same authors showed correlations between elevations in CBV and neurogenesis (230). Although a large number of studies report the beneficial effects of exercise on cerebral hemodynamics, a recent study that examined the acute effects of exercise intensity on peripheral vascular adaptations in healthy young adults reported unchanged CVR across all exercise conditions, including moderate-intensity exercise and sedentary controls (231). Importantly, this study was conducted in a very small and young sample of adults, limiting the translation to older adults. Another study in individuals with stable coronary heart disease reported inconsistent enhancements in cerebrovascular response following acute exercise (232). These findings highlight the complexity of the vascular response to exercise, especially in populations with pre-existing health conditions. Furthermore, although exercise is generally known to improve endothelial dysfunction, a key component in cardiovascular and cerebrovascular disease, whether higher exercise intensities confer greater benefits than moderate-intensity training (MIT) remains a topic of ongoing research (233).

The comprehensive benefits of exercise on various aspects of health and aging, including its impact on endothelial function and cerebral hemodynamics, are associated with maintenance (4,226) and recovery of cognitive function in older age (234–237). In an early exercise study, sedentary adults between 60 and 75 years of age were randomly assigned to a walking or stretching intervention and received neurocognitive assessments before and after 6 months. Compared to the stretching group, adults in the walking group demonstrated improvements in executive function (238). Additionally, age-related cognitive decline was attenuated (239) even when exercise interventions were undertaken in late adulthood (239,240). Furthermore, meta-analytic studies showed that the benefits of exercise on cognition extend to adults with MCI or dementia (237,241). Nevertheless, more recent studies challenge the efficacy of exercise in improving cognitive function in older adults (231,242,243). These incongruities highlight the need for more research into the underlying cellular and molecular mechanisms of exercise-induced benefits to the brain.

Effects of Different Exercise Intensities on the Cerebrovasculature

In the following section, we briefly describe how exercise-induced intensity-dependent metabolic energetic pathways may differentially impact the brain via distinct effects on CBF and cerebral waste product clearance.

To fuel physical activity, the human body relies on 3 energy systems: the phosphagen, anaerobic, and aerobic pathways, whose activations are dependent on the intensity and duration of the activity, and the availability and demand for oxygen (244). Although the 3 systems are simultaneously activated to varying degrees during exercise, one system will dominate depending on the activity type and energy requirements. For instance, short, intense activities such as heavy resistance training or sprinting lasting for 10–15 seconds activate the phosphagen system (244,245), whereas prolonged light-intensity training to MIT like swimming, cycling, or long-distance running is governed by the aerobic system (244). By contrast, anaerobic glycolysis becomes the dominant energetic pathway during high-intensity interval training (HIIT) (244).

Different energetic pathways exert a variety of effects on the hallmarks of aging, which in turn may affect the brain as described in the previous sections. To illustrate, the phosphagen and anaerobic systems, which are activated via resistance training and HIIT, can stimulate mitochondrial biogenesis, protect telomeres against attrition, and increase DNA repair mechanisms and proteostasis activity, while also regulating nutrient sensing via mitigation of insulin insensitivity (246). Activating the aerobic system enhances mitochondrial biogenesis and function and cytokine signaling pathways, leading to improved cell-to-cell communication, thus reducing inflammation and cellular senescence (246).

Additionally, it is well documented that MIT confers significant circulatory benefits including improvements in CBF (88,96,114,115,226,247), due to the more pronounced elevations in exercise-induced vascular shear stress (blood, velocity, and pressure) (248,249), studies show that HIIT results in markedly greater increases in cardiac output and vascular adaptations (250,251) and more substantial cardiovascular benefits (252) with greater reductions in cardiovascular risk factors (253).

Although research on the specific effects of HIIT on cerebral hemodynamics is limited (249), the vascular adaptations to HIIT suggest potential positive implications for CBF and cerebral waste product clearance. For instance, studies show that during incremental exercise, an initial increase in arterial partial pressure of carbon dioxide (PaCO₂) serves as a cerebral vasodilator (254). Furthermore, due to the dependence on glucose metabolism, as exercise intensity rises, the rise in PaCO₂ is followed by an increase in lactic acid and H+, which is quickly buffered by bicarbonate (HCO3−) and can be co-transported with lactate across the BBB (255). Consequently, the increase in H⁺ alters the concentration gradient between the brain and the blood, and stimulates cerebral uptake and utilization of lactate (256), which along with increasing levels of CO₂, enhances vasodilation and helps augment CBF (257,258). Interestingly, evidence from animal studies suggests that elevated levels of cerebral lactate in the perivascular fluid stimulate the glymphatic system, thereby increasing the clearance of cerebral waste products (259,260).

In summary, synergistic metabolic systems activate different energetic pathways and offer multipronged protection against the hallmarks of aging and associated endothelial, and vascular dysfunction (69,179), resulting in a more resilient vascular system, maintenance of CBF in aging (96,226), and enhanced clearance of cerebral waste products (259,260). This intricate relationship between various exercise intensities and aging emphasizes the significance of a holistic approach to health and well-being, and the need for more research into the differential effects of exercise intensities on the brain.

Conclusion

Aging is a multifactorial cellular and systemic process that is profoundly influenced by modifiable cardiovascular risk factors. The presence or absence of these risk factors exert direct and indirect effects on the cellular and molecular hallmarks of aging, further aggravating or enhancing these processes. In the vascular system, the aging cellular milieu leads to impairments in endothelial repair mechanisms and function, which consequently impair the cerebrovasculature and have downstream effects on cognitive function. Importantly, evolving evidence reveals the pivotal role of exercise in this complex interplay (Table 1; Figure 1). In this role, exercise not only mitigates cellular and molecular hallmarks of aging but also protects the cerebrovasculature and promotes the maintenance of brain health.

The conclusions of our narrative review must be tempered by the methodological limitations of currently published research in this field. First, the preponderance of studies we cited were based on cross-sectional or observational research, much of which was conducted in model animals. Although these studies offer valuable initial insights, they do not enable the causal inference that can only be established through more rigorous clinical trials in humans. Furthermore, studies with positive findings are more likely to be published, overshadowing those with null or negative results. Finally, research involving diverse populations, including varying age groups, ethnicities, and those with disease comorbidities, is lacking.

Despite the current wealth of knowledge, a comprehensive understanding of exercise effects on cerebrovascular pathology and repair mechanisms has remained fragmented, leaving several questions unanswered. Primarily, a relatively limited number of studies examined the effects of lifelong exercise and its effects on cerebrovascular function. The question of whether exercise undertaken after the onset of age-related cellular and cerebrovascular changes can confer similar benefits to lifelong CRF is unknown and requires empirical confirmation. Second, the dose–response relationship between exercise training and cerebrovascular and cognitive functions in older adults is unknown, and a comprehensive understanding of optimal exercise interventions remains elusive. Randomized clinical trials (261,262), which interrogate the effects of different exercise variables (eg, frequency, intensity, duration, modality) on the cerebrovasculature and brain function would provide necessary data to expand current knowledge of the neurobiology of aging and the mechanisms that underlie neuroprotection. Additionally, studies encompassing combined interventions that incorporate exercise with diet, senolytics, and other interventions that target the hallmarks of aging present promising avenues for future preventative or therapeutic interventions. To better understand how exercise affects cerebrovascular health and aging, future research must adopt comprehensive longitudinal studies focused on understanding the long-term implications of exercise interventions and their effects on the biological hallmarks of aging across different demographics.

Irrespective of the limitations of previous research, the current body of knowledge regarding the effects of exercise on cerebrovascular health is nevertheless promising. As a noninvasive, cost-effective, and holistic approach, optimized exercise interventions defend against cerebrovascular pathologies and their effects on cognition in aging. Given the rapidly expanding aging population and its projected societal impact, exercise may be a vital intervention to aid in the prevention or deferment of age-related cognitive impairments.

Funding

This work was supported by grants from the National Institute on Aging (T32 AG023480 and R21 AG073886). L.A.L. holds the Irving and Edyth S. Usen Chair in Geriatric Medicine at Hebrew SeniorLife.

Conflict of Interest

None.

Author Contributions

A.M.N. and L.A.L. conceptualized the review and made substantial contributions to this manuscript. A.M.N. was responsible for drafting and revising the manuscript. L.A.L. provided critical revisions and made substantial editorial contributions. A.M.N. and L.A.L. have reviewed and approved the final version of the manuscript.