Abstract

The increase in life expectancy is leading to a progressive rise in the percentage of older people in the general population, and consequently in the prevalence of chronic diseases, often leading to disability. Age-related modifications in cholesterol homeostasis, the increase in plasma cholesterol levels due to aging, represents a cardio- and cerebrovascular risk factor in adjunct to age itself. Direct knowledge about the pathophysiological alterations of cholesterol metabolism is limited. Clinical-experimental evidence about cholesterol lowering treatment suggests that the benefits observed in the general population are also observed in older age groups. However, patients enrolled in clinical trials often do not represent real-life clinical scenarios, limiting the generalizability of research findings. Issues of complexity and frailty are mostly inadequately addressed in published studies and guidelines. Further, effects of cholesterol itself and cholesterol lowering on cognitive function are still controversial. This narrative review focuses on current evidence about the pathophysiology and clinical implications of the relationship between cholesterol and aging. Some suggestions will be provided, underlining the need for careful, personalized evaluation of the patient’s functional status, along with clinical competence and geriatric skills.

INTRODUCTION

Aging of a population is the modification of the relative representation of older subjects compared to younger subjects, which translates into an increase in the population mean and median ages. The proportion of the world’s population over 65 years of age was 9.3% in 2020 and is expected to exceed 16% in 2050 1. The Italian population already has a high proportion of elderly subjects which is also expected to rise considerably, from 23% in 2020 to 36% in 2050.

The progressive increase in life expectancy is associated with a rise in the prevalence of chronic, non-communicable conditions 2. This burden represents an enormous challenge in terms of public health and resource allocation. Adequate management of chronic conditions, especially cardiovascular diseases and associated risk factors, will be essential for sustainable healthcare delivery and quality of life.

Chronological age is one of the major determinants of absolute cardiovascular risk 3-5, especially coronary heart disease. Other risk factors which are potentially treatable, include hypertension, high plasma cholesterol and diabetes. These conditions, whose prevalence steadily increases with ongoing aging, require appropriate management. The treatment of high cholesterol levels is a treatment strategy of paramount importance, particularly considering the widespread availability of effective and safe pharmacological options.

Among the elderly, other aspects, such as age-associated changes in drug pharmacokinetics and pharmacodynamics 6, need to be considered. As these changes can predispose the patient to drug-associated adverse events, often mediated by pharmacological interaction, lipid lowering treatment in older patients is still a matter of debate 7-9. The role of cholesterol in neurodegenerative conditions, such as Alzheimer’s disease, is also controversial 10.

This narrative, non-systematic review will present the available evidence about alterations of cholesterol metabolism associated with aging, with a focus on the cost-benefit balance and evaluation of the patients’ functional status. These issues may impact the most appropriate treatment choice.

AGING AND CHOLESTEROL HOMEOSTASIS

Theoretically, aging might associate with modifications in one, or more, of the different metabolic steps which control cholesterol homeostasis, ultimately changing circulating cholesterol levels. However, direct experimental evidence concerning age-associated alterations of cholesterol metabolism is relatively scarce, particularly in humans. This is likely due to the difficulty in identifying appropriate clinical-experimental models in older subjects 11.

Data about cholesterol absorption largely come from the analysis of circulating levels of hydroxylated sterols, campesterol and sitosterol, and provide conflicting evidence regarding the effects of aging 12-14. Data on cholesterol synthesis also derive from the analysis of circulating precursors (particularly lathosterol, and the lathosterol/cholesterol ratio) as indirect markers of biosynthesis. Again, evidence is conflicting, with some studies reporting no change in cholesterol synthesis with aging, and others suggesting a reduction in the biosynthetic process, mostly among the oldest age range 12-14.

Bile acid synthesis is a key regulator of the hepatic degradation of cholesterol, and modifications of this pathway may have a profound impact on cholesterol homeostasis. Data from human subjects, collected in vivo, suggest that a reduction in bile acid production may take place with aging 15,16. This hypothesis seems to support the analysis of the hepatic expression of cholesterol 7α-hydroxylase, the limiting enzyme of bile acid synthesis, and its transcriptional coactivators 17. Indirect data on circulating precursors in the biosynthetic pathway are not always consistent with this perspective, with reports of negative 17 or no correlations with aging 14. Different patient settings might account for these discrepancies.

These alterations might be expected to influence hepatic lipoprotein uptake and consequently circulating concentrations of cholesterol. Direct evidence with isotope analysis showed an association between aging and a reduction in the systemic clearance of low density lipoprotein (LDL) 18,19. Such a reduction in LDL clearance is consistent with the increased concentration of total and LDL-cholesterol observed in epidemiological studies 12,20. Interestingly, the correlation tends to disappear among the oldest age range 13,14.

Overall, a reduction in the requirement of metabolic substrates seems to be plausible in older age, which probably affects both bile acid and cholesterol production, and hepatic LDL uptake and consequently circulating LDL-cholesterol and total cholesterol levels, see Figure 1.

Age-associated alterations in the intestinal microbiota might also profoundly affect lipid metabolism 21,22. These aspects will be recalled later, along with the inherent implications in cognitive impairment.

THE ASSESSMENT OF FRAILTY

Frailty is characterized as a physiological decline across multiple body systems resulting in a lack of reserve for tolerating health stressors, and this decline is associated with an increased vulnerability to numerous adverse health outcomes 23.

Conflicting literature exists as to whether the presence of frailty predicts CVD. A recent meta-analysis found that frailty led to an increased risk of CVD 24. Even more recently, a large study found that frail individuals were at higher risk of a CVD event and CVD mortality compared to robust peers 25.

Frailty and CVD are hypothesized to have a bidirectional relationship, as chronic inflammation and insulin resistance share proposed processes of decline 26,27. Therefore, early identification of frail individuals may strengthen primary prevention efforts to reduce CVD risk. Given the relationship between frailty and CVD, similar interventions aimed at attenuating physiological decline may ameliorate the risk for both, and frail individuals may gain an additional benefit from CVD prevention compared to robust individual 25,28.

Assessment of frailty is instrumental in refining risk estimates and guiding patients toward personalized treatment plans, thereby maximizing the likelihood of a positive outcome. More than 20 tools have been developed to measure frailty 29. Most of these tools focus on one or more of the five core domains that define the Frailty Phenotype, first described by Fried et al. 23 including slowness, weakness, low physical activity, exhaustion, and shrinking. These elements can be objectively measured. The most frequently cited frailty scale in research settings is the Frailty Phenotype by Fried 23. Some of the other commonly used assessment scores include the Short Physical Performance Battery (SPPB) 30, the “Accumulation of Deficits” by Rockwood 31, the Multidimensional Prognostic Instrument (MPI) 32 and the Clinical Frailty Scale (CFS) 33-35. The SPPB and the “accumulation of deficits” by Rockwood, have been demonstrated to predict mortality and disability in patients with CVD 24-28. The MPI, a prognostic tool for hospitalized older patients, and the CFS, a scale of frailty based on clinical judgement and complemented by a visual chart, are the currently preferred frailty tools applied in clinical practice.

Frailty confers a 2-fold increase in mortality, an effect that persists even after adjustment for age and comorbidities. The relevance and impact of frailty has been demonstrated across a broad spectrum, including stable and subclinical CVD, heart failure, coronary syndromes, cardiac surgery, and transcatheter aortic valve replacement 27. However, when we consider lipid lowering treatment, frailty may represent a risk factor for statin-induced side effects, in particular muscle damage 36. This might relate to the frequent association of sarcopenia.

CHOLESTEROL-LOWERING AGENTS: REDUCTION OF CARDIOVASCULAR RISK IN OLDER PATIENTS AND SAFETY ISSUES

Age and circulating cholesterol levels are considered by all commonly employed tools for the prediction of cardiovascular risk 3-5. Therefore, the compresence of old age and high cholesterol levels has an additive effect on cardiovascular risk estimate, even if the relative impact of plasma cholesterol however is lesser in older patients, where age tends to have a prominent effect over other variables 37.

Proper evaluation of cardiovascular risk in old age is hampered by guidelines upper age ranges, which in many cases is referenced up to the sixth decade of life 38,39. Some more recent functions and algorithms at least partly overcome this problem. The updated version of the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines, which report the cardiovascular risk function of the European Systematic COronary Risk Estimation (SCORE) project, offers recommendations up to 70 years of age 40. SCORE also has an Older Persons function (SCORE O.P.) derived from the older age group enables the calculation of cardiovascular risk up to 90 years of age 41,42.

A correct estimation of cardiovascular risk may be essential to define the strength for a correct management of high cholesterol levels, and to avoid unnecessary lipid-lowering drug treatment. Most persons over 70 years old present high risk levels, and distinction between primary and secondary prevention might be labile.

Lifestyle intervention has proven to be effective and safe 43, but adherence to a correct exercise regimen and/or to an appropriate diet is difficult in old age. A number of studies have investigated the effects of therapeutic interventions on cardiovascular risk prevention. Most evidence comes from observational or interventional studies with competitive inhibitors of HMG-CoA reductase, the limiting enzyme of cholesterol synthesis, or statins.

Observational studies generally show a protective effect of statins, both in primary and in secondary cardiovascular prevention 7,44,45. Prospective randomized controlled trials, specifically addressing statin use in older patients, are extremely scarce. Only two trials were specifically designed to investigate the protective effects of statins in older patients. The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial utilized a standard dose of pravastatin versus placebo in a cohort of older patients, both in primary and secondary prevention 46. The Study Assessing Goals in the Elderly (SAGE) compared the effects of standard treatment (pravastatin) and intensive treatment (high dose atorvastatin) in patients with coronary heart disease 47. Both studies showed a significant protective effect of the intervention arm when compared to the control arm.

Even if direct evidence from specifically designed trials is limited, wider evidence from studies performed in the general population are available by means of subset, post-hoc analysis. The largest was the Heart Protection Study (HPS), which included a cohort of 5806 patients over 70 years old. In this cohort, a standard dose of simvastatin significantly reduced relative and absolute cardiovascular risk 48.

Many other studies have confirmed the protective effects of statins versus placebo, or of more “aggressive” statin treatment compared with standard therapy, in the older cohorts. Such evidence has been summarized in several reviews and meta-analyses 49-52. A protective effect of statin treatment was also shown on ischemic stroke recurrence 53.

A report from the Cholesterol Treatment Trialist Collaboration confirmed the reduction in major cardiovascular events, associated with statin treatment, in all age ranges, but with less direct evidence in primary prevention in subjects over 75 years old 54. Subsequent clinical-experimental evidence, including treatment with non-statin drugs, has further integrated this view.

A post-hoc analysis of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) compared the effects simvastatin alone with simvastatin plus ezetimibe treatment, a selective inhibitor of intestinal cholesterol absorption, in older subjects. This analysis showed an even greater reduction of events with combined intervention in patients older than 75 years versus younger patients. In this subgroup, an extremely low number to treat (NTT) was observed, and combined treatment was not associated with an increase in adverse events 55.

A prespecified secondary analysis of the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab (ODYSSEY OUTCOMES) trial also showed that the protective effects of the PCSK9 inhibitor alirocumab were clearly extended to older patients included in the study 56.

A more recent meta-analysis combined all statin trials with the studies including “non-statin” drugs, still keeping in mind that in the latter studies the interventional treatment was almost always on top of a maximal (or the maximal tolerated) statin regimen 57. This study included more than 21,000 subjects aged 75 or older. Once again, a clear reduction in the risk of major vascular events was found, and the protective effect appeared to be even greater (even if not significantly) in the older, compared with the younger cohort.

The evidence available in literature therefore suggests that lipid-lowering treatment with statins and/or other agents is protective against cardiovascular risk, also in older subjects. However, the observed benefits must be carefully weighed against possible drug-related adverse events, which are particularly frequent and clinically relevant in older subjects, due to changes in body composition, comorbidity and polypharmacy, which profoundly affect drug pharmacokinetics and pharmacodynamics 6,49.

Muscle damage represents the most frequent concern, for both physicians and patients. The causes of this phenomenon is likely to involve an impairment of cell respiration mediated by ubiquinone deficiency 29. When data from controlled trials were systematically analyzed, there was no evidence for a higher risk of myopathy in older people 58. Studies utilizing intensive drug dosages showed a dose-dependent increase in liver and muscle enzymes, although with limited clinical implications 47.

However, frail and complex patients are generally excluded from randomized studies 59 and limits the generalizability of study outcomes.

The 2002 American College of Cardiology (ACC) – American Heart Association (AHA) and National Heart, Lung, and Blood Institute (NHLBI) Statin Advisory document recommends cautiousness when considering statin treatment in older and frail patients 29. Careful evaluation of the functional status of the patient, is justified.

A relatively recent meta-analysis ruled out correlation between statin use and the incidence of malignancy 60. Recently, attention has focused on a higher incidence, or worsening, of type 2 diabetes mellitus 61,62. However, the benefits of statins largely outweigh the possible risks associated with the onset of diabetes, particularly for older subjects with a relatively limited life span.

Two ongoing clinical trials, the Statins in Reducing Events in the Elderly (STAREE) and the Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults (PREVENTABLE) studies, are specifically designed to address the risk-to-benefit ratio in older subjects 63,64. The results of these trials will be available in 2023 and in 2027 respectively and will hopefully help to shed more light on this field.

CHOLESTEROL HOMEOSTASIS AND COGNITIVE IMPAIRMENT

The highest levels of cholesterol accumulation in the body are in the central nervous system, which is a major structural component of cell membranes and myelin. The relationships between alterations in cholesterol metabolism and neurodegenerative disorders, in particular the different forms of dementia, are poorly defined. In theory, alterations in membrane cholesterol composition and intracellular cholesterol content might affect the functional properties of the nervous system.

The blood-brain barrier allows an efficient protection from exchange with circulating lipoproteins. Consequently, most brain cholesterol is synthesized locally, mainly within glial cells, and transferred to neurons by means of apoE-containing lipoproteins. The isoform apoE4 of this lipoprotein in particular has a low efficiency in transporting amyloid beta, and represents a genetic risk factor for Alzheimer’s disease (AD).

Excess cholesterol may be hydroxylated in the 24 position by neuronal 24-hydroxylase (CYP46A1). The hydroxysterol is then partially secreted into systemic circulation and is further metabolized by the liver 65,66.

Another degradation product of cholesterol detected in the brain is the 27(OH)cholesterol. The formation of this hydroxysterol is catalyzed by the ubiquitous enzyme 27-hydroxylase (CYP27A1) 67, Cholesterol 27-hydroxylation, which seems to be influenced by circulating levels of cholesterol 68, also represents the first step of the accessory pathway of bile acid synthesis. In its unbound form, 27(OH)cholesterol can be taken up by the central nervous system, where it can be converted into its acidic derivative, 7α(OH)-3-oxo-cholestenoic acid. This compound in turn can be resecreted into the systemic circulation and ultimately taken up by the liver. The metabolism of these two sterols and their relationship has been extensively investigated in neurodegenerative conditions, particularly in AD 69-72.

Evidence about hydroxysterol levels, both in plasma and in cerebrospinal fluid (CSF), is conflicting. Most of the findings, from experiments performed on animals and clinical studies in humans, suggest that the formation of 24(OH)cholesterol appears to represent a protective mechanism towards excess accumulation of cholesterol. Concentrations of 24(OH)cholesterol in the CSF increase in early stages of AD, but tend to decrease at more advanced stages of the disease, due to more severe atrophy. Plasma levels tend to mirror CSF concentrations 71,72.

In AD, CSF concentrations of 27(OH)cholesterol also tend to increase, possibly as a consequence of reduced degradation by oxysterol hydroxylases. Interestingly, modifications of 24(OH)cholesterol and 27(OH)cholesterol seem to follow distinct patterns in different neurological diseases. When the neurodegenerative process is prevalent, as is the case in AD, the increase in 24(OH)cholesterol prevails, whereas in conditions where damage of the blood-brain barrier predominates (such as in subarachnoidal hemorrhage) the increase in 27(OH)cholesterol is more evident than that of 24(OH)cholesterol 69.

The relationship between plasma cholesterol and the onset, or progression, of cognitive impairment has also been investigated. Most evidence in literature support a direct relationship between total (or LDL-) cholesterol and the risk of AD 69,73,74, particularly when observed along a wide temporal range, i.e. from midlife to older age. A reduction of high density lipoprotein (HDL)-cholesterol was also shown to be associated with dementia 75.

Pharmacological lowering of total and LDL-cholesterol might be expected to impact favorably on the incidence and progression of cognitive impairment, via a number of biological effects 76. Some reports suggest a protective effect of early statin use on the impairment of cognition over age 77,78 whereas other studies have found contradictory evidence, sometimes even suggesting that statins have a a detrimental effect on cognition 79.

The possibility of reverse causation should be taken into account in association studies, when both a protective or a detrimental effect of statins is suggested. Comorbid patients (i.e., with a greater likelihood to suffer from cognitive impairment) are more likely to receive lipid-lowering drugs 80 and, on the other, more compromised patients are less likely to be prescribed a statin, or to be adherent to its use 81. A recent large metanalysis addressing the association between statin use and cognitive function was inconclusive in any causation 82.

The timing of cholesterol-lowering treatment may play an important role. A Cochrane analysis showed that statin treatment in later life does not prevent cognitive decline. However, authors underlined the presence of significant bias in some studies 83.

The reduction of plasma total and LDL-cholesterol can certainly contribute to improve cardiovascular health and therefore, reduce the impact of age-related conditions 84, including cognitive impairment. Furthermore, the use of cholesterol-lowering drugs can be considered safe in most conditions 85. However, lipid lowering treatment is not recommended in advanced dementia, given patients’ limited life expectancy and an unfavorable cost-to-benefit ratio 86.

Recently, interest has also grown regarding proprotein convertase subtilisin/kexin type 9 (PCSK9), as it is capable of modulating circulating cholesterol levels. Data in literature have shown increased concentrations in CSF concentrations in AD compared to control subjects 87,88. The topic is of particular importance, considering the clinical implications inherent in the use of specific PCSK9 inhibitors as cholesterol-lowering drugs.

Preliminary findings from our research group revealed lower serum PCSK9 concentrations in AD patients, compared to subjects with mild cognitive impairment (MCI). In the CSF of AD patients, PCSK9 concentrations were lower in carriers of the apoE4 isoform, confirming its potential role in modulating the relationships between cholesterol metabolism and neurodegeneration 89.

It is difficult to reconcile the observed alterations with their possible clinical implications, and the role of PCSK9 in cognitive impairment conditions. It is interesting to recall, however, that treatment with PCSK9 inhibitors is devoid of negative effects on cognition, as demonstrated in the EBBINGHAUS trial with evolocumab 90.

In summary, the use of cholesterol-lowering drugs (including statins and PCSK9-inhibitors) can be considered safe in most conditions, and might be expected to have a protective effect on cardio- and cerebrovascular health, including neurodegeneration. However, lipid lowering treatment seems unjustified in most advanced diseases with reduced life expectancy 91.

DECISIONS CONCERNING LIPID LOWERING TREATMENT

As discussed in previous sections, the advantages of cholesterol-lowering treatment have to be carefully weighed against the risk of drug-related adverse events in a frequent context of polypharmacy. Published guidelines are often unsatisfactory in offering indications.

The 2018 document on blood cholesterol risk management, issued by several Northern America scientific societies, including the AHA and the ACC 92, suggests treatment initiation with a moderate-intensity statin. It recommends the interruption of statin treatment in patients over age 75 with an important frailty or complexity profile.

The 2019 ESC/EAS guidelines for the management of dyslipidaemias 40 and the 2021 ESC guidelines on cardiovascular prevention 41 state that statin treatment is recommended in older people with cardiovascular disease in the same way as in younger subjects. Statin treatment in primary prevention can be considered in a high-risk condition, and dose titration is recommendable. However, there is no direct mention about frailty or complexity, but a note of caution about possible adverse events and interactions.

In our opinion, the decision about whether to undertake cholesterol lowering treatment depends on the combination of the expected benefits in terms of risk reduction and the evaluation of the conditions which do not recommend drug treatment. In this view, the evaluation of frailty is of paramount importance.

Several reports in literature have attempted to systematically address this issue, through the adoption of schemes or flow charts, considering different aspects that influence the propensity to suggest treatment 49,93-97.

The presence of a high cardiovascular risk (or an established diagnosis of cardiovascular disease), together with good functional status, and limited and well controlled burden of comorbidity, will encourage drug initiation. However, frailty, overt disability, polypharmacy, cognitive impairment, or poor life expectancy will orient towards a more prudent attitude against drug treatment. Individual patient preference will also play a relevant role in the decision. Table I summarizes elements that favor the implementation of a pharmacological approach.

Interestingly, chronological age might be expected to weigh on both sides of the scale, being one of the most relevant and acknowledged cardiovascular risk factors and, at the same time, a major determinant of frailty and comorbidity.

The adoption of a specific tool for frailty estimation is therefore important. Depending upon the experience of the physician and local capabilities, a simple but adequate measurement of frailty can and should be performed in all clinical settings.

Recent evidence has addressed the issue of complexity and frailty with advanced statistical tools, such as multiple correspondence analysis and hierarchical clustering analysis, enabling the definition of specific clusters of disease 98. These reports confirm that patients more likely to receive cholesterol lowering treatment are at high cardiovascular risk and multimorbid, albeit cognitively preserved. The lowest prevalence in lipid-lowering drug use is associated with the oldest, frail patients with severe cognitive impairment.

We may expect that in some conditions the choice will be relatively simple: in patients with established cardiovascular disease but with a good functional status and prognosis, treatment will be strongly recommended and the overall attitude will approximate that adopted in middle-aged subjects. Similarly, treatment will appear largely unjustified in disabled and cognitively impaired patients, and generally in end-stage conditions 49. Clearly, many grey areas exist, where the experience of the physician and full patient history, including patients’ preferences, will orient the choice of lipid-lowering treatment. Finally, in the oldest age category, direct evidence is extremely limited 95.

Once the decision to undertake treatment has been taken, the choice of the appropriate drug and dosage is required, including the cholesterol lowering properties of available compounds and the potential for drug interactions and adverse events 99. As far as we know, this point has never been addressed directly in controlled clinical trials.

Considering the pharmacological properties of lipid lowering agents, the use of hydrophilic drugs, such as pravastatin, or drugs with a limited potential for pharmacometabolic interactions, such as fluvastatin 100, might be preferable. Pravastatin was utilized in the PROSPER trial, the only primary prevention trial specifically performed in older subjects 46, whereas direct evidence about the use of fluvastatin in the elderly is relatively scarce.

The association of statins with ezetimibe represents a plausible and rational alternative to unnecessary high statin dosages. Ezetimibe in adjunct to statin treatment enables target LDL-cholesterol levels more effectively than increasing statin dosage alone 101 and improves the efficacy profile compared to statin alone, as shown by a subgroup analysis in the IMPROVE-IT study 55.

The post-hoc analysis of the data of the Odyssey trial with a monoclonal antibody targeting PCSK9, alirocumab, also provides encouraging evidence 56, but it seems unlikely that this approach will be able to be adopted in older people, on a wide scale.

Despite published evidence from clinical studies and knowledge of the pharmacological and pharmacokinetic properties of these agents, prescription patterns in older people do not differ from the general population, as proven in real-life studies performed in hospitalized patients 80. However, there seems to be evidence of a recent trend towards a wider use of associations, including ezetimibe, in the elderly 98.

Less stringent LDL-cholesterol targets also seem to be reasonable in older patients, but this issue is still controversial. Recent ESC guidelines suggests the attainment of LDL-cholesterol levels below 100 mg/dl41. If we follow the widely accepted concept of “the lower, the better” LDL-cholesterol levels, we may reasonably pursue the lowest acceptable LDL-cholesterol levels which can be reached with minimal risks for the patients; this can also help to obtain a satisfactory patient adherence, which is instrumental in the achievement of good results in terms of cardiovascular prevention 102,103.

CONCLUSIONS

The impact of the aging process on cholesterol homeostasis is presently ill-defined. There is a scarcity of direct experimental evidence, particularly in humans. Further, the relationships between cholesterol metabolism, and its modifications induced by drug treatment, and cognitive function are also largely unclear. Currently, cognitive function and drug treatment is an active field of research, especially following the recent introduction of PCSK9 inhibitors in clinical practice.

Cholesterol lowering treatment has been demonstrated to be efficacious in cardiovascular prevention and safe, also in older subjects. Nonetheless, the benefits of drug treatment should be weighed against possible adverse events. Careful personalized evaluation of functional status is necessary, along with clinical competence and geriatric skills.

Clinical trials are still ongoing and will hopefully help to design the most appropriate management strategies for high cholesterol levels in older subjects. Well designed and conducted observational studies will also prove useful in examining the impact of treatment in a real-life context.

A personalized approach to cholesterol homeostasis is essential for the upcoming epidemiological transition, that will prove to be more challenging in the next few decades.

Acknowledgments

The Authors acknowledge the skillful contribution of Dr. Johanna Chester in the preparation of the manuscript.

Conflict of interest statement

The authors declare no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

MB: designed the overall layout of the paper; MB, GL, CM: wrote the initial draft of the manuscript and subsequently approved its final version.

Ethical consideration

Not applicable.

Figures and tables

Figure 1.Schematic illustration of the alterations in the main pathways controlling cholesterol homeostasis reported in association with the aging process. This representation illustrates the biomarkers of different metabolic steps, and is derived from published evidence in humans: including in vitro analyses, in vivo studies or assays of circulating hydroxysterols (see text for details; adapted from Bertolotti et al., 2019) 49.

High cardiovascular risk/secondary preventionChronological age < 75Good functional statusPreserved cognitive functionAbsence of systemic comorbidity, or well controlled diseaseNo polypharmacy (< 5 drugs)Individual preference by the patient Table I.Factors encouraging the adoption of a pharmacological based, cholesterol lowering approach in older subjects (adapted from Bertolotti et al., 2019; Strandberg et al., 2014) 49,93. ReferencesUnited Nations, Department of Economic and Social Affairs, Population Division. World Population Ageing 2019: highlights (ST/ESA/SER.A/430). 2019. Publisher Full Text National Institute on Aging – National Institutes of Health. Global Health and Aging. NIH Publication no. 11-7737. 2011. Wilson WF, D’Agostino RB, Levy D. Prediction of coronary heart disease using risk factor categories. Circulation. 1998; 97:1837-1847. DOI Conroy RM, Pyörälä K, Fitzgerald AP. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003; 24:987-1003. DOI Giampaoli S, Palmieri L, Chiodini P. The global cardiovascular risk chart. Ital Heart J Suppl. 2004; 5:177-185. Szadkowska I, Stanczyk A, Aronow WS. Statin therapy in the elderly: a review. Arch Gerontol Geriatr. 2010; 50:114-118. DOI Lemaitre RN, Psaty BM, Heckbert SR. Therapy with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) and associated risk of incident cardiovascular events in older adults: evidence from the Cardiovascular Health Study. Arch Intern Med. 2002; 162:1395-1400. DOI Kim CA, Kim DH. Statins provide less benefit in populations with high noncardiovascular mortality risk: meta-regression of randomized controlled trials. J Am Geriatr Soc. 2015; 63:1413-1419. DOI Ravnskov U, Diamond DM, Hama R. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016; 6:E010401. DOI Wee J, Sukudom S, Bhat S. The relationship between midlife dyslipidemia and lifetime incidence of dementia: a systematic review and meta-analysis of cohort studies. Alzheimers Dement. 2023; 15:E12395. DOI Morgan AE, Mooney KM, Wilkinson SJ. Cholesterol metabolism: a review of how ageing disrupts the biological mechanisms responsible for its regulation. Ageing Res Rev. 2016; 27:108-124. DOI Gälman C, Angelin B, Rudling M. Pronounced variation in bile acid synthesis in humans is related to gender, hypertriglyceridaemia and circulating levels of fibroblast growth factor 19. J Intern Med. 2011; 270:580-588. DOI Tilvis RS, Valvanne JN, Strandberg TE. Prognostic significance of serum cholesterol, lathosterol, and sitosterol in old age; a 17-year population study. Ann Med. 2011; 43:292-301. DOI Bertolotti M, Mussi C, Pellegrini E. Age-associated alterations in cholesterol homeostasis: evidence from a cross-sectional study in a Northern Italy population. Clin Interv Aging. 2014; 9:425-432. DOI Einarsson K, Nilsell K, Leijd B. Influence of age on secretion of cholesterol and synthesis of bile acids by the liver. N Engl J Med. 1985; 313:277-282. DOI Bertolotti M, Abate N, Bertolotti S. Effect of aging on cholesterol 7 alpha-hydroxylation in humans. J Lipid Res. 1993; 34:1001-1007. Bertolotti M, Gabbi C, Anzivino C. Age-related changes in bile acid synthesis and hepatic nuclear receptor expression. Eur J Clin Invest. 2007; 37:501-508. DOI Ericsson S, Eriksson M, Vitols S. Influence of age on the metabolism of plasma low density lipoproteins in healthy males. J Clin Invest. 1991; 87:591-596. DOI Millar JS, Lichtenstein AH, Cuchel M. Impact of age on the metabolism of VLDL, IDL, and LDL apolipoprotein B-100 in men. J Lipid Res. 1995; 36:1155-1167. Cohen JD, Cziraky MJ, Cai Q. 30-year trends in serum lipids among United States adults: results from the National Health and Nutrition Examination Surveys II, III, and 1999-2006. Am J Cardiol. 2010; 106:969-975. DOI Bonfili L, Cuccioloni M, Gong C. Gut microbiota modulation in Alzheimer’s disease: focus on lipid metabolism. Clin Nutr. 2022; 41:698-708. DOI Bertolotti M, Lonardo A, Mussi C. Nonalcoholic fatty liver disease and aging: epidemiology to management. World J Gastroenterol. 2014; 20:14185-14204. DOI Fried LP, Tangen CM, Walston J, Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001; 56:M146-M56. DOI Veronese N, Cereda E, Stubbs B. Risk of cardiovascular disease morbidity and mortality in frail and pre-frail older adults: results from a meta-analysis and exploratory meta-regression analysis. Ageing Res Rev. 2017; 35:63-73. DOI Farooqi M, Gerstein H, Yusuf S. Accumulation of deficits as a key risk factor for cardiovascular morbidity and mortality: a pooled analysis of 154,000 individuals. J Am Heart Assoc. 2020; 9:E014686. DOI Flint K. Which came first, the frailty or the heart disease? Exploring the vicious cycle. J Am Coll Cardiol. 2015; 65:984-986. DOI Afilalo J, Alexander KP, Mack MJ. Frailty assessment in the cardiovascular care of older adults. J Am Coll Cardiol. 2014; 63:747-762. DOI Boreskie KF, Rose AV, Hay JL. Frailty status and cardiovascular disease risk profile in middle-aged and older females. Exp Gerontol. 2020; 140:111061. DOI De Vries NM, Staal JB, van Ravensberg CD. Outcome instruments to measure frailty: a systematic review. Ageing Res Rev. 2011; 10:104-114. DOI Guralnik JM, Simonsick EM, Ferrucci L. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol. 1994; 49:M85-M94. DOI Rockwood K, Song X, MacKnight C. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005; 173:489-495. DOI Pilotto A, Ferrucci L, Franceschi M. Development and validation of a multidimensional prognostic index for one-year mortality from comprehensive geriatric assessment in hospitalized older patients. Rejuvenation Res. 2008; 11:151-161. DOI Basic D, Shanley C. Frailty in an older inpatient population: using the clinical frailty scale to predict patient outcomes. J Aging Health. 2015; 27:670-685. DOI Dent E, Kowal P, Hoogendijk EO. Frailty measurement in research and clinical practice: a review. Eur J Int Med. 2016; 31:3-10. Dent E, Martin FC, Bergman H. Management of frailty: opportunities, challenges, and future directions. Lancet. 2019; 394:1376-1386. DOI Pasternak RC, Smith SC, Bairey-Merz CN, American College of Cardiology; American Heart Association; National Heart, Lung and Blood Institute. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation. 2002; 106:1024-1028. DOI Prospective Studies Collaboration, Lewington S, Whitlock G, Clarke R. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007; 370:1829-1839. DOI Palmieri L, Panico S, Vanuzzo D. Evaluation of the global cardiovascular absolute risk: the Progetto CUORE individual score. Ann Ist Super Sanita. 2004; 40:393-399. Agostino RBD, Vasan RS, Pencina MJ. General cardiovascular risk profle for use in primary care. The Framingham Heart Study. Circulation. 2008; 117:743-753. DOI Mach F, Baigent C, Catapano AL. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020; 41:111-188. DOI Visseren FLJ, Mach F, Smulders YM. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021; 42:3227-3337. DOI Cooney MT, Selmer R, Lindman A. Cardiovascular risk estimation in older persons: SCORE O.P.. Eur J Prev Cardiol. 2016; 23:1093-1003. DOI Wilhelmsen L, Svärdsudd K, Eriksson H. Factors associated with reaching 90 years of age: a study of men born in 1913 in Gothenburg, Sweden. J Intern Med. 2011; 269:441-451. DOI O’Brien EC, Wu J, Schulte PJ. Statin use, intensity, and 3-year clinical outcomes among older patients with coronary artery disease. Am Heart J. 2016; 173:27-34. DOI Ramos R, Comas-Cufí M, Martí-Lluch R. Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study. BMJ. 2018; 362:k3359. DOI Shepherd J, Blauw GJ, Murphy MB, PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002; 360:1623-1630. DOI Deedwania P, Stone PH, Bairey Merz CN. Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the study assessing goals in the elderly (SAGE). Circulation. 2007; 115:700-707. DOI Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360:7-22. DOI Bertolotti M, Lancellotti G, Mussi C. Management of high cholesterol levels in older people. Geriatr Gerontol Int. 2019; 19:375-383. DOI Savarese G, Gotto AM, Paolillo S. Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis. J Am Coll Cardiol. 2013; 62:2090-2099. DOI Orkaby AR, Gaziano JM, Djousse L. Statins for primary prevention of cardiovascular events and mortality in older men. J Am Geriatr Soc. 2017; 65:2362-2368. DOI Yandrapalli S, Gupta S, Andries G, Cooper HA, Aronow WS. Drug therapy of dyslipidemia in the elderly. Drugs Aging. 2019; 36:321-340. DOI Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol. 2009; 8:453-463. DOI Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019; 393:407-415. DOI Bach RG, Cannon CP, Giugliano RP. Effect of simvastatin-ezetimibe compared with simvastatin monotherapy after acute coronary syndrome among patients 75 years or older: a secondary analysis of a randomized clinical trial. JAMA Cardiol. 2019; 4:846-854. DOI Szarek M, White HD, Schwartz GG. Alirocumab reduces total nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES Trial. J Am Coll Cardiol. 2019; 73:387-396. DOI Gencer B, Marston NA, Im K. Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials. Lancet. 2020; 396:1637-1643. DOI Iwere RB, Hewitt J. Myopathy in older people receiving statin therapy: a systematic review and meta-analysis. Br J Clin Pharmacol. 2015; 80:363-371. DOI Crome P, Lally F, Cherubini A. Exclusion of older people from clinical trials: professional views from nine European countries participating in the PREDICT study. Drugs Aging. 2011; 28:667-677. DOI Collins R, Reith C, Emberson J. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016; 388:2532-2561. DOI Cui JY, Zhou RR, Han S. a network meta-analysis. J Clin Pharm Ther. 2018; 68:556-570. DOI Mansi IA, Chansard M, Lingvay I. Association of statin therapy initiation with diabetes progression: a retrospective matched-cohort study. JAMA Intern Med. 2021; 181:1562-1574. DOI Zoungas S, Curtis A, Spark S, STAREE investigator group. Statins for extension of disability-free survival and primary prevention of cardiovascular events among older people: protocol for a randomised controlled trial in primary care (STAREE trial). BMJ Open. 2023; 13:E069915. DOI Joseph J, Pajewski NM, Dolor RJ, PREVENTABLE Trial Research Group. Pragmatic evaluation of events and benefits of lipid lowering in older adults (PREVENTABLE): Trial design and rationale. J Am Geriatr Soc. 2023. DOI Björkhem I. Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J Intern Med. 2006; 260:493-508. DOI Loera-Valencia R, Goikolea J, Parrado-Fernandez C. Alterations in cholesterol metabolism as a risk factor for developing Alzheimer's disease: potential novel targets for treatment. J Steroid Biochem Mol Biol. 2019; 190:104-114. DOI Javitt NB. 25R,26-Hydroxycholesterol revisited: synthesis, metabolism, and biologic roles. J Lipid Res. 2002; 43:665-670. Bertolotti M, Del Puppo M, Corna F. Increased appearance rate of 27-hydroxycholesterol in vivo in hypercholesterolemia: a possible compensatory mechanism. Nutr Metab Cardiovasc Dis. 2012; 22:823-830. DOI Sandebring-Matton A, Goikolea J, Björkhem I. 27-Hydroxycholesterol, cognition, and brain imaging markers in the FINGER randomized controlled trial. Alzheimers Res Ther. 2021; 13:56. DOI Kölsch H, Heun R, Jessen F. Alterations of cholesterol precursor levels in Alzheimer’s disease. Biochim Biophys Acta. 2010; 1801:945-950. DOI Nury T, Yammine A, Ghzaiel I. Attenuation of 7-ketocholesterol- and 7β-hydroxycholesterol-induced oxiapoptophagy by nutrients, synthetic molecules and oils: Potential for the prevention of age-related diseases. Ageing Res Rev. 2021; 68:101324. DOI Giudetti AM, Romano A, Lavecchia AM. The controversial role of 24-S-Hydroxycholesterol in Alzheimer’s disease. Curr Alzheimer Res. 2016; 13:198-205. DOI Schilling S, Tzourio C, Soumaré A. Differential associations of plasma lipids with incident dementia and dementia subtypes in the 3C study: a longitudinal, population-based prospective cohort study. PLoS Med. 2017; 14:E1002265. DOI Anstey KJ, Ashby-Mitchell K, Peters R. Updating the evidence on the association between serum cholesterol and risk of late-life dementia: review and meta-analysis. J Alzheimers Dis. 2017; 56:215-228. DOI Zuliani G, Cavalieri M, Galvani M. Relationship between low levels of high-density lipoprotein cholesterol and dementia in the elderly. The InChianti study. J Gerontol A Biol Sci Med Sci. 2010; 65:559-564. DOI Wanamaker BL, Swiger KJ, Blumenthal RS. Cholesterol, statins, and dementia: what the cardiologist should know. Clin Cardiol. 2015; 38:243-250. DOI Steenland K, Zhao L, Goldstein FC. Statins and cognitive decline in older adults with normal cognition or mild cognitive impairment. J Am Geriatr Soc. 2013; 61:1449-1455. DOI Poly TN, Islam MM, Walther BA. Association between use of statin and risk of dementia: a meta-analysis of observational studies. Neuroepidemiology. 2020; 54:214-226. DOI Roy S, Weinstock JL, Ishino AS. Association of cognitive impairment in patients on 3-Hydroxy-3-Methyl-Glutaryl-CoA reductase inhibitors. J Clin Med Res. 2017; 9:638-649. DOI Bertolotti M, Franchi C, Rocchi MB. Prevalence and determinants of the use of lipid-lowering agents in a population of older hospitalized patients: the findings from the REPOSI (REgistro POliterapie Società Italiana di Medicina Interna) Study. Drugs Aging. 2017; 34:311-319. DOI Power TP, Ke X, Zhao Z. Clinical characteristics, patterns of lipid-lowering medication use, and health care resource utilization and costs among patients with atherosclerotic cardiovascular disease. Vasc Health Risk Manag. 2018; 14:23-36. DOI Adhikari A, Tripathy S, Chuzi S. Association between statin use and cognitive function: a systematic review of randomized clinical trials and observational studies. J Clin Lipidol. 2021; 15:22-32.E12. DOI McGuinness B, Craig D, Bullock R. Statins for the prevention of dementia. Cochrane Database Syst Rev. 2016; 2016:CD003160. DOI Wang R, Fratiglioni L, Liang Y. Prevalence, Pharmacological Treatment, and control of cardiometabolic risk factors among older people in Central Stockholm: a population-based study. PLoS One. 2015; 10:E0119582. DOI Ott BR, Daiello LA, Dahabreh IJ. Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. J Gen Intern Med. 2015; 30:348-58. DOI Onder G, Landi F, Fusco D. Recommendations to prescribe in complex older adults: results of the CRIteria to assess appropriate Medication use among Elderly complex patients (CRIME) project. Drugs Aging. 2014; 31:33-45. DOI Zimetti F, Caffarra P, Ronda N. Increased PCSK9 cerebrospinal fluid concentrations in Alzheimer’s disease. J Alzheimers Dis. 2017; 55:315-320. DOI Adorni MP, Ruscica M, Ferri N. Proprotein convertase subtilisin/kexin type 9, brain cholesterol homeostasis and potential implication for Alzheimer’s disease. Front Aging Neurosci. 2019; 11:120. DOI Bertolotti M, Zimetti F, Chiari A. Modifications in the concentrations of PCSK9 in serum and in cerebrospinal fluid in patients with cognitive disorders. 121st National Meeting, Italian Society of Internal Medicine, Virtual Edition. 2020. Giugliano RP, Mach F, Zavitz K, EBBINGHAUS Investigators. Cognitive function in a randomized trial of evolocumab. N Engl J Med. 2017; 377:633-643. DOI Schultz BG, Patten DK, Berlau DJ. The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms. Transl Neurodegener. 2018; 7:5. DOI Grundy SM, Stone NJ, Bailey AL. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019; 73:3168-3209. DOI Strandberg TE, Kolehmainen L, Vuorio A. Evaluation and treatment of older patients with hypercholesterolemia: a clinical review. JAMA. 2014; 312:1136-1144. DOI Gazzola K, Vigna GB