Frailty is the term commonly utilized to describe the geriatric syndrome that exposes the elderly to increased risk of negative health-related events. The frailty phenotypes (PF: physical or CF: cognitive) have demonstrated to predict the major negative health-related outcomes in the old population and show extensive similarities with sarcopenia (for PF) or dementia (for CF). However, the role of neurophysiological and biological factors contributing to the physical and cognitive frail condition, and in particular in which way mitochondrial dysfunction, as well as the hypertrophic and atrophic pathways assessed by genes expression, metabolomics and microbiota composition are contributing to these frail conditions, are still under debate. Therefore, the aim of this trial will be to make evidence based on the behaviors and the strategies that promote healthy lifestyle and successful human aging.

In the majority of the world, the population is living to a greater age. However, older age is usually associated with elevated risk of several pathologies, as well as age-related organ dysfunctions, which in turn can accelerate functional impairments, disability, or death. To identify this geriatric syndrome the term frailty phenotype has been commonly utilized. In particular, the frailty phenotype can be distinguished in physical frailty (PF) phenotype or cognitive frailty (CF) phenotype.

Despite several groups of researchers tried to develop preventive interventions to counteract the physical and cognitive frail condition of elderly, the success of this task has been tempered by the lack of standardized, and universally agreed protocols. Moreover, the limited knowledge of the neurophysiological, and biological determinants of these conditions has precluded important advances in the research of this domain.

Many factors combine to achieve a successful aging: genetics, health care and healty lifestile. Therefore, the aim of the current trial will be to understand the behaviors and the strategies that promote healthy lifestyle and successful human aging.

Oldest old participants with CF and PF will be selected from the neurorehabilitation unit of the University Hospital of Verona (Italy). Healthy oldest old and young participants will be recruited from the section of Movement Sciences of the University of Verona.

After a first phase of neurophysiological and biological examinations that will involve all the 4 groups, only CF and PF participants will be randomly assigned to an intervention program (physical exercise, physical+cognitive exercise or control). Frail participants assigned to exercise groups will then perform 1 year of intervention, 3 days per week, 1 hour per day. Afterwards, the three groups of intervention will undergo the same neurophysiological and biological examinations of the beginning of the study.

Inclusion Criteria:

• YH: 30 healthy young (20-25 years old) participants. They must be free of any disease.
• OH: 30 healthy oldest old (80-90 years old) participants. They must be free of any neural or physical disease and any severe chronic disease (CODP, Heart Failure) that can compromise exercise.
• PF: 30 oldest old (80-90 years old) participants. They must be characterized by functional deficits (sarcopenia, osteoporosis and muscle weakness) without cognitive impairment. Additionally, participants cannot be affected by any severe chronic disease that compromise exercise.
• CF: 30 oldest old (80-90 years old) participants. They must be characterized by mild cognitive impairment (MCI) and subjective cognitive decline without functional deficits. Additionally, participants cannot be affected by any severe chronic disease that compromise exercise.

Exclusion Criteria YH

• Any medication
• Any disease
• General: pregnancy, addictive or previous addictive behavior defined as the abuse of cannabis, opioids or other drugs, carrier of infectious diseases.
• For TMS: Epilepsy, metallic prosthesis, malignant tumor

Exclusion Criteria OH

• Heart failure, angina, pulmonary disease.
• Cognitive frailty (MCI, Alzheimer) or physical frailty (musculoskeletal diseases)
• General: coagulation disorders, pregnancy, addictive or previous addictive behavior defined as the abuse of cannabis, opioids or other drugs, carrier of infectious diseases, suffering from musculoskeletal diseases, suffering from mental illness, inability to cooperate, subjects suffering from known cardiac conditions (e.g., pacemakers, arrhythmias, and cardiac conduction disturbances) or peripheral neuropathy. Moreover, subjects suffering from diabetes, arthritis and under medication will be scored according to specific criteria.
• Assumption of any anticoagulant medication
• Assumption of antiplatelet medications in high dose (es: acetylsalicylic acid >200mg x day)
• For TMS: Epilepsy, metallic prosthesis, malignant tumor
• For MRI: pacemaker, internal defibrillator or other ferromagnetic implants

Exclusion Criteria PF

• Simultaneous presence of physical frailty and cognitive impairment (CDR=0.5)

• For exercise testing and training: heart failure, angina, pulmonary disease.

• General: coagulation disorders, pregnancy, addictive or previous addictive behavior defined as the abuse of cannabis, opioids or other drugs, carrier of infectious diseases, suffering from musculoskeletal diseases, suffering from mental illness, inability to cooperate, subjects suffering from known cardiac conditions (e.g., pacemakers, arrhythmias, and cardiac conduction disturbances) or peripheral neuropathy. Moreover, subjects suffering from diabetes, arthritis and under medication will be scored according to specific criteria.

• The T-scores for the whole body and PA-projection total spine parameters: According to the World Health Organization (WHO) recommendation, participants will be diagnosed as having osteoporosis when the minimum T-score, measured at any site, will be less than -2.5, osteopenia if T-score between -1 and -2.5 and normal if T-score will be greater than -1 according to the World Health Organization guideline. Diagnosis will be made on basis of lowest T score at any measured site (T score ≥-1 SD = Normal; T score between -1 and -2.5 SD = Low bone mass, and T Score ≤-2.5 SD = Osteoporosis). T-score reference values are provided by the DXA scanner manufacturer.

• Assumption of any anticoagulant medication

• Assumption of antiplatelet medications in high dose (es: acetylsalicylic acid >200mg x day)

• For TMS: Epilepsy, metallic prosthesis, malignant tumor

• For MRI: pacemaker, internal defibrillator or other ferromagnetic implants

• Decline a priori to participate in the intervention Phase 2 of the study

• Cut-off exclusion criteria of PF:

  • Fried's Frailty Phenotype: < 3 positive characteristics
  • Timed-up-and-go test: <10 sec
  • The Multidimensional Prognostic Instrument (MPI): < 0.66 score
  • The GAITRite system: > 0.9 m/s
  • Groningen Frailty Indicator: <4

Exclusion Criteria CF

• Simultaneous presence of physical frailty and cognitive impairment (CDR=0.5)

• For exercise testing and training: heart failure, angina, pulmonary disease.

• General: coagulation disorders, pregnancy, addictive or previous addictive behavior defined as the abuse of cannabis, opioids or other drugs, carrier of infectious diseases, suffering from musculoskeletal diseases, suffering from mental illness, inability to cooperate, subjects suffering from known cardiac conditions (e.g., pacemakers, arrhythmias, and cardiac conduction disturbances) or peripheral neuropathy. Moreover, subjects suffering from diabetes, arthritis and under medication will be scored according to specific criteria.

• The T-scores for the whole body and PA-projection total spine parameters: According to the World Health Organization (WHO) recommendation, participants will be diagnosed as having osteoporosis when the minimum T-score, measured at any site, will be less than -2.5, osteopenia if T-score between -1 and -2.5 and normal if T-score will be greater than -1 according to the World Health Organization guideline. Diagnosis will be made on basis of lowest T score at any measured site (T score ≥-1 SD = Normal; T score between -1 and -2.5 SD = Low bone mass, and T Score ≤-2.5 SD = Osteoporosis). T-score reference values are provided by the DXA scanner manufacturer.

• Assumption of any anticoagulant medication

• Assumption of antiplatelet medications in high dose (es: acetylsalicylic acid >200mg x day)

• For TMS: Epilepsy, metallic prosthesis, malignant tumor

• For MRI: pacemaker, internal defibrillator or other ferromagnetic implants

• Decline a priori to participate in the intervention Phase 2 of the study

• Cut-off exclusion criteria of CF:

  • Mini Mental State (MMSE): cut-off 23.8
  • FCSRT: IFR (immediate free recall) cut off <19.59; ITR (immediate total recall) cut off<35; DFR (delayed free recall) cut off <6.31; DTR (delayed total recall) cut off<11; index of sensitivity of cueing cut off<0.9; Number of intrusions cut off>0
  • Digit Span: cut off 3.75
  • Digit Span Reversal (WAIS): cut off 2.65
  • Rey-Osterrieth Complex Figure Test: cut off copy 28.88 - cut off
  • deferred reproduction 9.47
  • Trial Making Test A(ENB2): cut off >93 sec; TMT B (ENB2): cut off >282 sec; TMT B-A (ENB2): cut off>186 sec
  • Frontal Assessment Battery (FAB): cut off <13.4
  • Phonemic Fluency (ENB2): cut off 3
  • Clock Test: cut off <6.25
  • Time up and Go TUG-COG: cut off >15sec
  • Cognitive Function Instrument (partly for the caregiver): no cut-off
  • Neuropsychiatric Inventory (for the caregiver): cut-off >0
  • Geriatric Depression Scale: cut-off>10