Pathophysiology, epidemiology and therapy of ageing

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Internal Medicine / Gerontology and Geriatrics.

Aim and focus

In the coming years, human ageing will be one of the biggest challenges faced by industrialized countries. While our life expectancy continues to rise, doctors will be confronted with an increasing number of older patients with acute and chronic diseases that manifest themselves in the second half of life. According to recent Dutch projections, the number of people over 65 years of age will increase to 4,8 million by 2040 on a total population of 18 million (27%). The growing group of older people exhibits a wide variability in geriatric vulnerability. Patients with impairments in cognition, mobility and lack of a social network, are at increased risk for functional decline and loss of independence, also after disease-specific treatment(s).  Due to the lack of evidence-based medicine for the care and cure of older patients, little is known about the efficacy of the clinical tools and instruments that are employed to improve adverse health outcomes in the heterogeneous group of older patients.

Therefore, the main aim of the research line is to develop evidence-based medicine for older patients by unravelling the pathophysiology and therapy of the ageing process and its associated diseases.

The clinical and fundamental research approaches can be viewed as two sides of a spectrum and are naturally intertwined in a bedside-to-bench-and-back continuum. They are an important component of the LUMC profile area ‘Ageing’.  Understanding of the pathophysiology of ageing is crucial for developing clinically relevant diagnostics and therapies for older patients and, reciprocally, clinical dilemmas and older patients are the basis of our research into the ageing process. In this research line we apply advanced epidemiological methods to study etiology, prediction, diagnostics and intervention. We focus on studies in older people in the whole spectrum from healthy to diseased in four research topics: evidence-based medicine of older patients, metabolic health, the heart-brain connection, and thyroid hormone function.

Evidence-based medicine for older patients
The clinical research theme aims to quantify the geriatric heterogeneity of various patient populations, to develop predictive tools for adverse outcomes and subsequently to integrate this prediction in clinical decision making, to investigate how ageing affects determinants and outcomes of disease, and to develop and implement evidence-based interventions to improve outcomes for the older patient. The research theme is relatively young, yet has established multiple prospective research cohorts. In the prospective Acutely Presenting Older Patients (APOP) study, which we will use for developing and validating prediction tools to identify the most vulnerable older patients for various adverse outcomes, we have recently included and followed a cohort of almost 3000 patients aged 70 years and older presenting to the Emergency Department of our own and other hospitals. An implementation study is ongoing to test effects of implementation of a screening program that was based on results of this study. Together with the LUMC Division of Nephrology and the HAGA Hospital, we have set up the Cognition in Older Persons with End-stage renal disease (COPE) study, where predictors of treatment success or adverse outcomes (especially cognitive decline) are studied in older patients with end stage renal disease. Extensive geriatric and neurocognitive testing is performed in combination with imaging of the brain and heart, to unravel the determinants of functional and cognitive decline in this vulnerable age group. The regional COPE study has sparked the initiation of a national registry for older patients with End Stage Renal Disease (the POLDER study). In the Triage of Elderly Needing Treatment (TENT) study, we use data from a recently implemented routine and standardized geriatric screening, in all patients of 70 year and older from the Departments of Surgery, Cardiology, Ear Nose and Throat (ENT), and Gynaecology who need surgery, chemotherapy or radiotherapy. A standardized geriatric test battery at baseline is combined with a standardized follow-up scheme for mortality and other adverse outcomes and implemented in multiple hospitals in the region. Together with the Department of Oncologic Surgery, Medical Oncology and Psychiatry we continue to collaborate on quantifying outcomes in elderly patients with breast cancer and colon cancer.

Metabolic health
In the research theme pathophysiology and therapy of the ageing process, we aim to dissect the mechanisms for maintenance of physiological integrity and homeostasis into old age.  Central focus areas are the interactions between different components of internal physiology, including the brain, the cardiovascular system, the musculoskeletal system, and the peripheral organs and tissues involved in glucose and lipid metabolism, as well as the neuro-endocrine pathways that are involved in this crosstalk.
The crosstalk between the brain and the peripheral organs and tissues involved in energy, glucose and lipid metabolism is investigated in a highly translational setting within the EC funded projects Switchbox and HUMAN. Studies in Switchbox encompass the analysis of 24h rhythms of hormones, metabolites, physiological parameters and their interplay in participants from the Leiden Longevity Study. We also perform pioneering experiments to assess the effect of intranasal application of neuropeptides on brain function and metabolism in younger and older adults. Studies in HUMAN investigate mechanisms underlying metabolic health by means by Mendelian randomization and multi-layer –omics approaches in large datasets. Studies in NEO (Netherlands Epidemiology of Obesity Study) investigate aetiology of cardiovascular and metabolic diseases among overweight or obese individuals. The NEO study is a collaboration between multiple departments of the LUMC and is coordinated by the department of Clinical Epidemiology.
Using our FP7 funded PHASE GWAS of all participants of PROSPER (n=5200) we use published SNPs for polygenetic risk scores to assess causal associations with cardiovascular outcomes. In this research line we also participate in numerous meta-analyses of GWAS studies of various outcomes.
In collaboration with Philips b.v., we develop, validate and study algorithms of physical activity as measured using accelerometry across various cohorts. The recently funded the EIT Health project "Vitality" aims to integrate various digital health platforms and study feasibility and business opportunity.

The heart-brain connection
In addition to Alzheimer’s disease (AD) causing dementia, vascular disease is increasingly recognized as an independent contributor to cognitive impairment. Emerging data show that a healthy hemodynamic balance in the heart-brain axis is crucial for maintaining functional and structural integrity of the brain. This offers a possible therapeutic trajectory since diseases of the heart are modifiable and sometimes curable, whereas no curative treatments are available for cognitive dysfunction to date. In several of our large elderly cohort studies (PROSPER, Leiden 85-plus Study, Leiden Longevity Study) we study the effect of hemodynamic indicators (e.g. blood pressure, heart rate variability, use of antihypertensives) on health and disease, in particular, brain structure and function). In collaboration with the Department of Radiology we started the CVON-project “the Heart-Brain Connection”, where patients with heart failure, vascular cognitive impairment or carotid occlusive disease are assessed for brain and heart MRI-abnormalities and cognitive dysfunction. Moreover, we finalised the ZonMW funded DANTE study, a randomised clinical trial in which older patients with mild cognitive deficits were taken of their antihypertensive drugs for three months which did affect cognitive function. In a follow-up study, we will study whether the same intervention is effective in reducing neuropsychiatric symptoms in nursing home patients with dementia. A novel research collaboration (with Leiden University, Philips, CbusineZ  and the municipality of The Hague) that has the goal to further investigate the different features of the heart-brain connection and to study the physiology of the interplay between these features is “The Hague collaboration”, which is aimed at establishing an infrastructure (including MRI and biobanking) for continuous recruitment of  a heterogeneous group of older subjects from The Hague area (persons of diverse ages, educational and socio-economic status).

Thyroid hormone function
Thyroid hormones play an important role in all stages of life, including old age. Thyroid status is influenced by many  different cues, including day-night rhythm, nutritional status, environmental temperature, physical or emotional stress, and pathophysiological conditions, such as acute inflammation and critical illness, making the interpretation of thyroid function tests in older people challenging. Whether or not there should be replacement therapy for subclinical changes in thyroid status during ageing is a matter of ongoing debate. Such decisions require in depth knowledge of thyroid hormone signalling and how thyroid hormones regulate key processes, particularly those that have been hypothesised to be closely correlated to variations in healthy ageing,  such as effects on metabolism, cognition, heart rate, muscle wasting, and bone loss. The role of thyroid hormone in maintenance and functional decline of the central nervous system, musculoskeletal system and cardiovascular and metabolic systems is investigated in a European setting in the EC funded projects TRUST and THYRAGE and on a national level in the IEMO 80-plus thyroid trial. The THYRAGE project addresses the questions how hormone signalling maintains and integrates homeostasis at various physiological levels during ageing and how thyroid hormone signalling can be optimally modulated during ageing in specific tissues. To achieve these aims, THYRAGE integrates cross-disciplinary expertise from clinical and basic scientists, endocrinologists, neuroscientists, gerontologists, and industry-based peptide scientists. Studies at the LUMC include pharmacological challenge studies with recombinant human thyroid stimulating hormone and thyroid hormone. The LUMC also investigates the effect of changes in thyroid status on markers of tissue turnover in different human studies, including the TRUST and IEMO 80-plus thyroid trials.
Our objective is to identify biomarkers and processes that define individual risk susceptibility for better disease prevention, health promotion, therapy development, and the management of co-morbidities.

The overall aim of the research line is to develop evidence-based medicine for older patients by unravelling the pathophysiology and therapy of ageing and its associated diseases.

Specific objectives include:

  • To develop predictive tools for adverse outcomes in older patients in routine care and to design, develop and implement strategies to prevent adverse outcome(s) in high risk patients.
  • To answer questions of causal inference in older populations via application of advanced epidemiological methods.
  • To dissect mechanisms for maintenance of physiological homeostasis into old age, including neuro-endocrine and metabolic pathways.
  • To investigate the contribution of hemodynamic dysregulation to cognitive decline and dementia in old age.
  • To study the age related changes in thyroid function, its associates and therapies.

Position in international context

Principle Investigators have established collaborations with excellent international research groups, including:

  • Prof. dr. Andrzej Bartke, USA. Collaborations in the area of growth hormone/insulin/IGF-1 and longevity (Leiden Longevity Study, rodents).
  • Dr. Kate Bennett, Sweden. Collaboration in the area of metabolomics and metabolic health (HUMAN).  
  • Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
  • Prof. Simon Conroy and Dr. Jay Bannerjee, UK. Collaboration in the area of Geriatric Emergency Medicine (APOP).
  • Prof. dr. Barbara Demeneix, France. Collaborations in the area of thyroid hormone and longevity (Switchbox, HUMAN, THYRAGE).
  • Prof. dr. Csaba Feteke and Prof. dr. Balaz Gereben, Hungary. Collaborations in the area of thyroid hormone and longevity in rodents and humans (Switchbox, THYRAGE).
  • Dr. Kevin Mills, UK. Collaboration in the area of proteomic analyses and metabolic health (HUMAN).
  • Prof. Nicolas Rodondi, Switzerland. Collaboration in the field of thyroid (TRUST, IEMO 80+ thyroid trial, Thryoid collaboration international).
  • Dr. Behnam Sabayan, USA. Collaboration in the area of the heart-brain connection (Prosper, CVON-HBC).
  • Prof. David Stott and Prof. Naveed Sattar, UK. Collaboration in the field of cardiovascular risk in older patients (PROSPER).
  • Prof. dr. Rudi Westendorp, Denmark. Collaborations in the area of healthy ageing and of thyroid hormone and ageing (Switchbox, TRUST, THYRAGE).
Van Heemst has a leading role in several international research consortia that focus on the integration of clinical and basic studies, notably the H2020 project THYRAGE of which she is project coordinator (2016-2021).
Mooijaart was elected (2016) chairman of the special interest group of Geriatric Emergency Medicine of the European Union Geriatric Medical Society and as such is co-chair of the European Task Force for Geriatric Emergency Medicine.
Trompet is project leader of the international GIST consortium, which investigates the pharmacogenetics of statin treatment.

Content / highlights / achievements

Main scientific findings ordered per research topic.

Evidence-based medicine for older patients

  • Only 7% of all published randomized controlled trial specifically target older patients, and only a minority of these trials report adequately on which older patients were included.
  • Geriatric impairments such a physical, mental or social impairments and frailty associate with poor health outcomes in older patients with end stage renal disease, head and neck cancer and oesophageal cancer.
  • We developed and validated an instrument that predicts adverse outcome in older Emergency Department patients, independent of disease severity.
Metabolic health
  • Circulatory levels of GGT were found not be causally related to type 2 diabetes.
  • Large genetic studies found support for a role of the central nervous system in obesity susceptibility.
  • Genetic loci associated with effectiveness of statin treatment to lower LDL-C and increase HDL-C were identified.
The heart-brain connection
  • Higher visit-to-visit variability in LDL-C was associated with lower cognitive performance, lower cerebral blood flow, and greater white matter hyperintensity load.
  • It was found that in older persons with mild cognitive deficits, discontinuation of antihypertensive treatment did not improve cognitive, psychological, or general daily functioning at the 16-week follow-up.
  • It was found that higher visit-to-visit variability in blood pressure independent of average blood pressure was associated with impaired cognitive function in old age.
Thyroid hormone function
  • In a RCT comprising 752 older persons with subclinical hypothyroidism, it was found that levothyroxine treatment provided no apparent benefits. 
  • Human (familial) longevity was found to be associated with increased TSH secretion.
  • Potential mechanisms by which thyroid hormone might impact lifespan were identified from literature.

Future themes

Evidence-based medicine for older patients

  • Establishing multiple national registries that include uniform collection of clinical data and biomarkers from older patients.
  • Development and assessment of guidelines for specific treatments in older patients with various diseases
Metabolic health
  • Analysis of cross-correlations between pituitary hormones, physiological parameters and tissue maintenance.
  • Investment of effects intranasal application of neuropeptides on brain function and metabolism. 
  • Genetic and multi-layer –omics analyses of the (patho)physiology of cardio-metabolic health and disease.
Heart-brain connection
  • Assessment of the association between the cardiovascular and hemodynamic factors in relation to brain structure and cognitive functioning.
  • Assessment of the effects of temporary discontinuation of antihypertensive treatment in older patients with cognitive impairment in nursing home: a randomised controlled trial.
Thyroid hormone function
  • Assessment of the role thyroid hormone in maintenance and functional decline of the central nervous system, musculoskeletal system and cardiovascular and metabolic systems.
  • Assessment of the possibilities of stopping thyroid hormone treatment in older patients with hypothyroidism.

Cohesion within LUMC

Our research program is performed in the context of the LUMC research theme ‘Ageing’. Through this framework we closely collaborate with the divisions of:

  • Cardiology
  • Molecular Epidemiology
  • Oncology
  • Orthopaedic surgery
  • Psychiatry
  • Public health and primary care
  • Radiology
  • Surgery
In addition, we have active collaborations with the divisions of:
  • Clinical Epidemiology
  • Emergency Medicine
  • Endocrinology
  • Immunohematology and Blood Transfusion
  • Molecular Cell Biology
  • Nefrogeriatrics