Cognitive decline naturally occurs with healthy ageing. However, accelerated decline can have grave implications, as increased cognitive decline is associated with increased risk of developing Alzheimer's disease-related dementias (ADRDs). Currently, ADRDs are a key research priority for the National Institute on Aging. As the USA's population continues to grow older, the prevalence of cognitive decline is likely to rise. Studies support a direct correlation between cerebrovascular function and cognition (Thorin-Trescases et al. 2018). This is plausibly due to age-related changes in large elastic artery stiffness and vascular endothelial function. In young adults, large peripheral elastic arteries (e.g. the aorta and carotids) serve to dampen large swings in arterial blood pressure produced with each heartbeat. This, in turn, slows the velocity of blood as it flows towards the resistance arteries of the brain. The endothelium and vascular smooth muscle cells within these resistance vessels then sense this change in pulse pressure, dilating in response (Thorin-Trescases et al. 2018). However, these mechanisms become impaired with advancing age. A common hallmark of vascular ageing is increased large elastic artery stiffness. Vascular hypertrophy derived from lifelong distension and recoil of the vessels induces arterial remodelling, whereby elastin fibres within the vascular walls become fragmented and are replaced with stiffer collagen fibres, decreasing the ability of the arteries to absorb changes in pulse pressure (Thorin-Trescases et al. 2018). Subsequently, pulse pressure increases and impairs vascular endothelial function, altering the ability of the endothelium to respond to vasodilatory stimuli, such as CO2. Along with being an independent risk factor for cardiovascular disease, increased arterial stiffness is associated with increased risk of cognitive decline. One measure of cerebrovascular function which is sensitive to changes in arterial compliance is cerebrovascular reactivity (CR), or the ratio of cerebral artery blood flow response to a CO2 stimulus. Importantly, CR decreases with advancing age and is directly associated with cognitive decline (Thorin-Trescases et al. 2018). Therefore, CR may not just be a measure of cerebrovascular function; it may provide insight into current and future cognitive health. Spaceflight is believed to be an accelerated model of vascular ageing. Indeed, data from different studies support age-related morphological and functional changes to astronaut vasculature over the course of long duration (6 months) spaceflight missions. For one 6-month mission on the International Space Station (ISS), echography was used to measure the intima–media thickness (IMT) in the carotid and femoral arteries of astronauts preflight, inflight and postflight (Arbeille et al. 2016). Increased IMT is considered a risk factor for cardiovascular diseases (e.g. atherosclerosis), and IMT increases progressively with age (Arbeille et al. 2016). For these astronauts, the average increase in IMT was 12%. This increase in IMT is indicative of accelerated ageing, as a 12% increase in IMT is equivalent to 20–30 years of vascular ageing (Arbeille et al. 2016). Although this increase in IMT is alarming, it is unclear whether these changes to IMT will persist long-term, as Arbeille et al. (2016) only noted elevated IMT 4 days postflight. In another study, Hughson et al. (2016) investigated how spaceflight alters carotid artery stiffness via carotid artery distensibility coefficient and -stiffness index (two indicators of arterial stiffness). After 6 months of spaceflight aboard the ISS, all astronauts had a decreased carotid artery distensibility coefficient (20% change, preflight to postflight) and increased -stiffness index (25% change, preflight to postflight), indicating increased arterial stiffness (Hughson et al. 2016). Importantly, this study demonstrated that even with unaffected blood pressure regulation, spaceflight was able to induce age-related increases in arterial stiffness, equivalent to 10–20 years of normal vascular ageing (Hughson et al. 2016). However, similar to IMT, these changes may be short-lived, as arterial distensibility rebounded 4 days postflight to similar preflight values (Arbeille et al. 2017). This recovery suggests that vascular remodelling (e.g. elastin fragmentation and collagen deposition) likely did not occur over the course of 6 months. Additionally, Hughson et al. (2016) only performed pre- and postflight measures and, as such, no inferences can be made about whether functional changes to carotid arterial stiffness occurred during spaceflight. As the authors of these studies suggest, this increase in IMT and vascular stiffness may be due to a secondary mechanism, which remains to be elucidated. Although the mechanism driving these changes is unclear and no firm conclusions can be made about whether these changes persist longitudinally, results from Arbeille and Hughson suggest that spaceflight-related headward fluid shift appears to induce age-related changes to astronaut vasculature for the duration of spaceflight. Along with accelerated vascular ageing, long-duration spaceflight (or spaceflight analogue) has been associated with other negative sequelae, such as the development of optic disc oedema and thickening of the retina surrounding the optic nerve head, characteristics of spaceflight associated neuro-ocular syndrome (Laurie et al. 2020). Similar to accelerated vascular ageing, the weightlessness and subsequent cephalic fluid shift astronauts experience is believed to contribute to this syndrome by increasing intracranial pressure (ICP). Additionally, due to confined quarters, most astronauts are exposed to mildly elevated (3–5 mmHg) ambient CO2 levels (hypercapnia) during long periods of spaceflight. For Laurie et al. (2020), this chronic exposure is a concern, as some research has suggested that elevated ambient increases arterial , which vasodilates the cerebral arteries and increases ICP (Laurie et al. 2020). Together, this elevation in ambient CO2 and headward fluid shift are believed to contribute to spaceflight-related ocular impairments via increased ICP. CR can provide information about cerebral artery blood flow velocity and cerebrovascular conductance (how well blood flows through cerebrovascular circulation at a given arterial blood pressure), including under extreme conditions such as spaceflight or spaceflight analogues. However, whether a headward fluid shift and elevated ambient together affect cerebrovascular haemodynamics is unclear. Thus, in an article in a recent issue of The Journal of Physiology, Laurie et al. (2020) sought to investigate the relationship between chronic hypercapnia and 6° head-down tilt bed rest (HDTBR; a common spaceflight analogue) on CR. To test whether mildly elevated and HDTBR can change cerebrovascular dynamics, 11 healthy subjects (5 females, 6 males) were recruited to participate in a 30-day HDTBR study. For the duration of the study, research subjects remained in a strict, 6° head-down tilt position in a mild hypercapnic (4 mmHg ) environment. At four different time points during the 30-day HDTBR, middle cerebral artery blood flow velocity and cerebrovascular conductance were measured to calculate cerebrovascular reactivity. When the authors compared pre-hypercapnic/HDTBR measurements to those of post-hypercapnic/HDTBR recovery, they observed no significant changes in CR at any time point (Laurie et al. 2020). Even under extreme conditions, CR appears to be unaffected by mildly hypercapnic environments and chronic HDTBR. Given that a headward fluid shift can increase carotid artery stiffness and CR is sensitive to changes in arterial compliance, it would logically follow that CR would decrease over the course of the study. Thus, this null result is rather perplexing. One potential explanation is that actual spaceflight elicits greater changes in CR than that of spaceflight analogues, such as HDTBR. Furthermore, a longer latency period may be required to observe significant augmentation. For a short (1–2 weeks) Neurolab (STS-90) Space Shuttle mission, Iwasaki et al. (2007) observed improvements in cerebrovascular autoregulation in astronauts (Iwasaki et al. 2007); however, during long-duration spaceflight, this was not the case. When astronauts returned from a 147 (±49)-day mission aboard the ISS, astronauts presented with impaired autoregulation and CO2 reactivity (Zuj et al. 2012). Importantly, for the short- and long-duration spaceflight studies, changes in cerebrovascular dynamics were only observed postflight, whereas Laurie et al. (2020) demonstrated no longitudinal change in CR whilst subjects underwent chronic HDBTR and mild hypercapnia. Moreover, it may be that cerebrovascular dynamics can adapt to an increased ICP from spaceflight, albeit for short durations. Whether there is a particular time point at which CR begins to decline during spaceflight is still unclear; however, if feasible, a follow-up study in which inflight changes to CR were tracked longitudinally aboard a future ISS mission could answer this lingering question. Although cerebrovascular autoregulation appeared unaffected by sustained HDBTR and chronically elevated mild hypercapnia, CR may still be a useful measure for other models of accelerated ageing, such as anthracycline-based chemotherapy. Compared to spaceflight, cancer is a regular occurrence, with ∼1.8 million new cancer cases projected to occur in 2020. Similar to cognitive decline, cancer risk also increases with advanced age. Anthracyclines are the front-line chemotherapeutic agent for various forms of common cancers and, sadly, the same mechanisms that make anthracyclines such effective chemotherapeutics are also the reason they are considered models of accelerated ageing. Similar to ageing adults, patients who undergo anthracycline-based chemotherapy also experience an ADRD-like form of cognitive impairment. More colloquially known as ‘chemo brain,’ patients who undergo anthracycline treatment exhibit cognitive impairments normally associated with advancing age, such as memory and learning deficits. Although anthracyclines are considered accelerators of ageing in multiple cell types, the effects of anthracyclines on measures of cerebrovascular function (i.e. CR) are understudied. Given that CR decreases with advancing age and is associated with cognitive decline, understanding how CR is influenced by anthracyclines may allow us to understand the underlying mechanism(s) behind anthracycline-associated cognitive decline. Previous studies suggest that anthracyclines increase reactive oxygen species (ROS) and inflammation in multiple cell types. Excessive oxidative stress and inflammation can lead to increased large elastic artery (aorta) stiffening, which can elevate systolic blood pressure. Indeed, many studies support that increased arterial stiffness and high blood pressure can increase the risk of cognitive decline (Thorin-Trescases et al. 2018). Given that CR is highly dependent on arterial elasticity, it may be that anthracycline-induced ROS and inflammation is affecting cerebrovascular function, ultimately contributing to cognitive impairment (Fig. 1). To explore the relationship between anthracycline-derived chemo brain and cerebrovascular function further, certain clinical and preclinical outcomes for oxidative stress, inflammation, vascular health and cognitive function could be measured. To identify anthracycline-related changes, physiological phenotyping could be performed on survivors of anthracycline-based chemotherapy and compared to age-matched, untreated controls. Ideally, this would be done a few ways. Cultured cerebrovascular smooth muscle cells (cVSMC) would be exposed to plasma from patients and controls; from there, antioxidant enzyme (e.g. superoxide dismutases (SODs), catalase) abundance could be measured. Since excessive ROS is generally accompanied by a compensatory increase in expression of antioxidant enzymes, this measure could serve as a surrogate marker of oxidative stress. Additionally, following plasma exposure, these cVSMC could be washed and cultured again to collect the culture medium, which could be used to determine how plasma exposure influences cytokine (IL-1, TNFα, etc.) secretion from these cells. Finally, atomic force microscopy could be performed on these cVSMC to see if increases in ROS and inflammation from anthracycline patient plasma increase cellular stiffness. To correlate these changes to cerebrovascular function, these assays would be accompanied by complete macrovascular phenotyping, including carotid–femoral pulse wave velocity (a measure of large elastic artery stiffness) and blood pressure. Additionally, cerebral blood flow (a surrogate measure of total brain blood flow) and CR (flow response to a stimulus (i.e. CO2), as described in Laurie et al. 2020) would provide a comprehensive measure of the cerebral vasculature. Lastly, cognitive function would be measured using the NIH toolbox, a validated modality to measure cognitive function. To gain mechanistic insight, preclinical studies could then reverse translate these clinical observations to a mouse model. Three groups could be used: old control (as a reference group), young control, and young (age-matched) treated mice receiving a dose of anthracycline (e.g. doxorubicin/Adriamycin). Ideally, measures of arterial stiffness (in vivo aortic pulse wave velocity, ex vivo intrinsic mechanical stiffness (elastic modulus) of the arterial wall), and cognitive function (Barnes maze and novel object recognition) would be performed. Unfortunately, CR cannot be measured in mice per se, which would be a limitation in the translatability of preclinical findings. Since the hippocampus is the memory centre of the brain and is thought to be impacted by anthracyclines, the results from the vascular phenotyping could then be correlated to hippocampal neuroinflammation. This could be done by measuring ROS and inflammatory cytokine abundance in middle cerebral artery via electron paramagnetic resonance (EPR) and ELISA (IL-1, TNFα, etc.), respectively. Another measure of hippocampal neuroinflammation that may be employed is hippocampal transcriptomics, whereby gene expression related to cognition and learning/memory could be measured in old, young and young anthracycline-treated mice. The hippocampal transcriptome in the anthracycline mice could then be compared to the old (reference) group of mice, which could validate that anthracycline chemotherapy can be a model of brain ageing. Finally, an additional measure would be anthracycline accumulation within peripheral and neural tissues. Currently, results are mixed about whether therapeutic doses of anthracyclines cross the blood–brain barrier. Anthracyclines such as doxorubicin/Adriamycin are rapidly cleared from the blood within 24–72 h, making them difficult to measure in circulation. Thus, performing these measurements in peripheral tissues could further elucidate whether anthracyclines act in a direct or systemic fashion, potentially providing therapeutic targets. Hypothetically, if the deleterious phenotypes observed in chemo brain are effects derived from peripheral insults (e.g. oxidative stress and inflammation in vascular smooth muscle cells), treatment with therapeutics such as exogenous antioxidants (e.g. ascorbic acid) or anti-inflammatories (e.g. NSAIDs) may provide feasible modalities to prevent or ameliorate the downstream phenotypes of chemo brain. In conclusion, CR as an in vivo measure of cognitive function may help to elucidate how anthracyclines contribute to cognitive decline in cancer patients. As industrialized societies continue to age, the prevalence of cognitive decline, cancer and anthracycline-induced cognitive impairment are likely to rise. A primary risk factor for cancer development is ageing and, with projections of close to 2 million new cancer cases in 2020 alone, CR may become an essential measure within this clinical population. Although no changes were observed in subjects undergoing chronic hypercapnic conditions in the Laurie et al. (2020) study, it may be that some modalities are more potent evokers of change in CR than others. Age-accelerating anthracyclines may be one of those potent stimuli and, as such, should be the subject of future investigations. None. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. NIH award: HL151022 (Z.S.C.).