Ongoing & future activities

The European population is rapidly aging and the number of older adults aged 70 and older is predicted to increase by 40% by 2030, as will the number of older adults with age-related chronic diseases. The growing number of older adults with age-related chronic diseases poses a challenge on European societies and health care systems. There is an increasing need for population-based longitudinal studies that can illuminate factors that contribute to healthy and independent aging.

The original DO-HEALTH trial (KEK-ZH-2012-0249) was a large, randomized, double-blind, placebo-controlled, multi-centre clinical trial that enrolled 2157 community-dwelling men and women 70 years and older to examine the individual and the combined benefit of 2000 IU vitamin D/day, 1 g of omega-3 fatty acids/day and a simple home exercise program (see https://clinicaltrials.gov/ct2/show/NCT01745263).

Community-based cohorts of comprehensively phenotyed older adults provide a unique opportunity to shed light on long-term determinants of healthy and independent aging. Thus, the DO-HEALTH cohort will be a continuation of the trial without intervention and will elucidate long-term determinants of healthy, active and independent aging in European community-dwelling older adults. The main emphasize of the cohort will be to determine the risk factors, to quantify the incidence and to describe the trajectories of incident frailty, impaired mobility, loss of independence and age related morbidity (e.g. heart arrhythmia, type 2 diabetes, falls, fractures). Additionally, the cohort will continue to investigate the primary endpoints of the original trial like the risk and incidence of injurious falls (bone); functional decline (muscle); high blood pressure (cardiovascular); cognitive decline (brain); and the rate of any infection (immunity). Moreover, the cohort will include and extend key secondary and exploratory endpoints of the original trial such as incidence and prevalence of anemia, sarcopenia, cardiovascular diseases, type 2 diabetes and cancer. The DO-HEALTH cohort will take advantage of the established infrastructure, the validated procedures and the established contact with the DO-HEALTH trial participants.

Due to current funding limitation, only DO-HEALTH participants who were recruited at the study centers in Zurich and Basel will be included in the cohort at this point in time. Also the follow-up will not be the same for both centers. If additional funding becomes available, we plan to further extend the cohort to other study centers of DO-HEALTH.

The comprehensive phenotyping of the DO-HEALTH trial will be extended into the cohort including the collection on life style factors such as diet, quality of life and physical activity, as well as health-related data on co-morbid conditions as well as a standardized assessment of multiple organ functions, physical, cognitive and mental function using surveys and standardized health assessments. As in the DO-HEALTH trial, the data collection in the DO-HEALTH cohort entails minimal risks and burdens to the participants. Only well-established assessment tools, which are routinely used in clinical practice or have previously been used in the research setting among older adults, will be employed. Notably, most of the cohort assessments have already been used in the original DO-HEALTH trial.

This project aims to elucidate long-term determinants of healthy, active and independent aging in community dwelling older adults living in Europe. The cohort will also gather information concerning the extended long-term effects of the three DO-HEALTH interventions (omega-3, vitamin D, and the simple home exercise program) on the primary and several secondary and exploratory endpoints of the original DO-HEALTH trial.  However, the main aim of the cohort is to study the trajectories of aging. Specifically, the cohort aims to determine the risk factors and early biomarkers for healthy and active aging and to describe the risk factors and early biomarkers of frailty, impaired mobility, loss of independence, institutionalization, all-cause hospitalization, age related morbidity (e.g. falls, heart arrhythmia, type 2 diabetes, fractures) and all-cause mortality. In addition, the cohort will explore risk factors that contribute to changes in quality of life, sleep quality, mental health and cognition (e.g., adherence to MIND diet, and anemia and iron deficiency to prevent or delay the further progression of cognitive decline.) Also, resilience and coping strategies related to the Covid-19 pandemic and its impact on cognitive function and mental health will be investigated (integrated sub-study (DO-HEALTH cohort MINDful, see document “MINDful_ShortInformation_Ethics”)). Finally, the DO-HEALTH cohort will assess the impact of polypharmacy, individual medications, as well as therapeutic competition (drug-disease interaction) on the health of older adults based on outcomes such as cognitive health, health-related quality of life and frailty.

Primary endpoints:

The DO-HEALTH-Cohort will address 5 primary endpoints:

1. Incidence of functional decline (muscle)
2. Incidence of injurious falls (bone)
3. Incidence of high blood pressure (cardiovascular)
4. Incidence of cognitive decline (brain)
5. Incidence of infections (immunity)

Secondary and exploratory endpoints:

The DO-HEALTH-Cohort will assess additional endpoints that support the primary endpoints and extend to other organ systems:

1. Incidence and prevalence of frailty
2. Incidence and prevalence of impaired mobility
3. Incidence and prevalence of functional dependency
4. Incidence and prevalence of anemia or iron deficiency (DO-HEALTHcohort and DO-HEALTHcohort-MINDful substudy)
5. Incidence and prevalence of any cardiovascular disease
6. Incidence and prevalence of heart arrhythmia
7. Incidence and prevalence of atrial fibrillation
8. Incidence and prevalence of heart failure, cardiomyopathy, heart valves abnormalities
9. Incidence of stroke
10. Incidence and prevalence of Type 2 diabetes
11. Incidence and prevalence of dementia
12. Incidence and prevalence of osteoarthritis
13. Incidence and prevalence osteoporosis
14. Incidence and prevalence of sarcopenia, osteosarcopenia
15. Incidence and prevalence of any gastrointestinal disease
16. Incidence and prevalence of gastroesophageal reflux disease (GERD)
17. Incidence and prevalence of any micronutrient deficiency (Vitamins, Minerals and fatty acids)
18. Incidence and prevalence of knee buckling
19. Incidence and prevalence of chronic pain
20. Incidence and prevalence of subjective memory complaints
21. Incidence and prevalence of hearing impairment
22. Incidence and prevalence of depression (DO-HEALTHcohort and DO-HEALTHcohort-MINDful substudy)
23. Incidence and prevalence insomnia
24. Incidence and prevalence of chronic inflammation
25. Incidence and prevalence of polypharmacy
26. Incidence and prevalence of inappropriate medication prescription
27. Incidence and prevalence of age related morbidity by individual drug use (e.g. Proton-Pump-Inhibitors, anticoagulants, benzodiazepines, antibiotics)
28. Incidence and prevalence of malnutrition
29. Incidence and prevalence of urinary incontinence
30. Incidence and prevalence of impaired quality of life (DO-HEALTHcohort and DO-HEALTHcohort-MINDful substudy)
31. Incidence and prevalence of functional decline
32. Incidence of fractures
33. Incidence of all-cause hospitalization
34. Incidence, prevalence and trajectories of frequent health care utilization
35. Incidence of nursing home placement
36. Incidence of cancer (any cancer, gastro-intestinal, breast cancer in women, prostate cancer in men)
37. Incidence of all-cause mortality
38. Prevalence of MIND diet adherence (DO-HEALTHcohort-MINDful substudy)
39. Prevalence and Incidence of Mild Cognitive impairment (DO-HEALTHcohort-MINDful substudy)
40. Dual-tasking gait variability (DO-HEALTHcohort-MINDful substudy)
41. Prevalence of confirmed Covid-19 cases (DO-HEALTHcohort-MINDful substudy)
42. Prevalence of Covid-19 vaccinated participants (DO-HEALTHcohort-MINDful substudy)
43. Prevalence of reported subjective cognitive decline (DO-HEALTHcohort-MINDful substudy)
44. Covid-19 related resilience (DO-HEALTHcohort-MINDful substudy)
45. Covid-19 related stress (DO-HEALTHcohort-MINDful)
46. Covid-19 related coping behaviours (DO-HEALTHcohort-MINDful)

Biomarker Endpoints:

1. Proteins: total protein, albumin, ferritin, soluble transferrin receptor
2. Inflammation: hs-CRP, TNF-α, IL10, IL-8, IL-6, IL-1ß
3. Blood count to assess hematologic abnormalities (RBC, Hb, WBC, Tc) with erythrocyte indices (MCV etc.), machine differential (Granuloc., lymphocyte) and reticulocytes.

Further biomarker endpoints will depend on the availability of further funding. If additional funding is secured, we plan to perform the same analyses as in the original DO-HEALTH trial. Thus, the same amount of blood as in the original DO-HEALTH trial (75 ml) will be collected at the annual visits in the DO-HEALTH-cohort, and stored in the DO-HEALTH biobank.

If additional funding becomes available, the following biomarkers will be additionally analyzed:

4. Bone: Serum Calcium, Serum phosphate, 25(OH)D, intact PTH, urinary calcium/creatinine ratio (second spot urine), Beta-Crosslaps serum, P1NP, sclerostin
5. Muscle: myostatin
6. Cardiovascular: Troponin T, NT-proBNP, homocysteine, CK, cholesterol, HDL-cholesterol, triglycerides
7. Gastro-intestinal: ALT, AST, gGT, alkaline phosphatase, bilirubin
8. Glucose-metabolic: fasting glucose, insulin
9. Kidney: serum creatinine; creatinine urine; calcium urine; calcium/creatinine ratio in second spot urine, albumin urine, serum urea, uric acid
10. Global Health: Ions: sodium, potassium, chloride, magnesium
11. Hormones: TSH, fT4, fT3, cortisol
12. Vitamins: folic acid, vitamin B12, 25(OH)D
13. Post-trail adherence to Vitamin D an Omega-3: serum 25(OH)D measured by two methods (automated assay and gold standard HPLCMS/MS). Plasma PUFA concentrations (EPA, AA, DPA, DHA) measured by a sensitive and selective assay based on gas chromatography coupled to mass spectrometry detection (GC-MS).
14. Whole genome and biomarker sequencing
15. HLA typing
16. Telomere length
17. DNA methylation-based biomarkers: Horvath’s clock — 353 CpGs Multi-tissue DNAm age estimator, Hannum’s clock — 71 CpGs Single-tissue DNAm age estimator, Levine’s clock — 513, CpGs DNAm PhenoAge
18. Metabolomic Analysis

This is a multicenter prospective cohort study that aims to elucidate long-term determinants of healthy, active and independent aging in European community dwelling older adults. The participants are offered a multi-stage study design with options, depending on the study center and the extent of participation.

In Zurich, this observational study will have semi-annual in-person follow-up visits alternating on-site and by phone. Alternatively, the participants can also choose the semi-annual in-person follow-up design by phone only (on-site visits replaced by phone interview) (see figure 1; A and B). Or they even can choose the one-time design. Here they have the option to choose between a one-time visit on-site (“baseline”) or a phone interview (see figure 2; A and B).

Follow-up period: At least one year (depends on the amount of the available funding). Since incidence of all-cause mortality is an important endpoint of the cohort, the aim is to extend the follow-up period until its full assessment, hence after the last participant has deceased.

Inclusion criteria:

• Former participation in the DO-HEALTH clinical trial study

Exclusion criteria:

• Inability or unwillingness to give written informed consent
• Medical condition that would make the results of the tests/assessments unreliable and/or would put too much burden to the participant, and/or leads to safety concerns.

Study Site	ZH	ZH	BS	ZH/BS
Visit	on-site	phone call	on-site	phone interview
Blood withdrawal, spot urine	x		x
Electrocardiography (ECG)	x
DXA: Body composition (bone, fat and lean mass) (V0, V1, etc.)	x (every 12mt)
DXA: Bone mineral density (BMD) at the lumbar spine and hip (both sides) (V0, V2, etc.)	x (every 24mt)
DXA: vertebral morphometry / vertebral fracture assessment (VFA) (V0, V2, etc.)	x (every 24mt)
Physical Examination: – Current status of organs – Vision – Heart rate	x		x	x (only 4 vision questions)
Medical History: – Height and weight – important medical events – health related events and healthcare utilization – Post DO-HEALTH trial compliance	x		x	x (only Post DO-HEALTH trial compliance)
Medication	x	x	x	x
– Medical events – Falls – Fractures – Infections	x		x
Follow-up phone call data collection: shortened questionnaires about falls, fractures, infections, hospitalization and list of incident events		x		x
Cognitive assessment (MoCA)	x	x (only 4 orientation items)	x	x (only 4 orientation items)
Physical Test – Short Physical Performance Battery – Gait speed and repeated chair stand test – Grip strength	x		x
Gait analyses incl. single and dual task assessment			x
Hearing test	x			x (only 4 questions)
Memory Complaints Questionnaire (MAC-Q)	x		x
Quality of life (EQ5D-3L)	x		x	x
Mental health, depression (GDS, excerpt)	x	x (short GDS)	x	x (short GDS)
Oral health (GOHAI)	x		x
Musculoskeletal pain (McGill pain map)	x		x
Joint map	x		x
Activities of daily living (PROMIS-HAQ)	x		x
Frailty (SHARE-FI)	x	x	x	x
Gastro-intestinal symptoms (Rome III questionnaire)	x		x
Physical activity (NHS, excerpt)	x	x (only question 5)	x	x (only question 5)
Comorbidities (Sangha’s instrument)	x (V0 only)		x
Sunlight exposure questionnaire	x		x
Symptomatic osteoarthritis (knee, hip, and hand; joint map) – knee buckling questionnaire – KOOS -HOOS -QuikDash (excerpt)	x		x
Sleep quality (Insomnia Severity Index)	x		x
International prostate symptom score (IPPS) – only for men	x		x
Urinary Incontinence (QUID) – only for women	x		x
Subjective happiness scale	x		x
ZAM Cognitive Activities Questionnaire	x		x
Diet assessment (FFQ) at cohort baseline (V0) and after three years only	x (V0, V3, etc.)		x
Demographic information – living situation – community, friends, caregiver – activities	x	x (help with daily tasks)	x	x (help with daily tasks)
Covid-19 Pandemic Stress Scale (CPSS)	x (next sche-duled event, only one time)		x	x (next sche-duled event only one time)
Brief Resilience Scale (BRS)	x (next sche-duled event, only one time)		x	x (next sche-duled event only one time)
Pandemic Coping Scale (PCS)	x (next sche-duled event, only one time)		x	x (next sche-duled event only one time)
Covid-19 experience and resilience: Semi-structured interview (qualitative assessment – sub-set of participants)	x (next sche-duled event, only one time)			x (ZH only, next scheduled event, only one time)