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Luigi Ferrucci, M.D., Ph.D., Senior Investigator |
| Biography: Dr. Luigi Ferrucci is a geriatrician and an epidemiologist who conducts research on the causal pathways leading to progressive physical and cognitive decline in older persons. In September 2002, he became the Chief of the Longitudinal Studies Section at NIA and the Director of the Baltimore Longitudinal Study on Aging. Dr. Ferrucci received a Medical Degree and Board Certification in 1980, a Board Certification in Geriatrics in 1982 and Ph.D. in Biology and Pathophysiology of Aging in 1998 at the University of Florence, Italy. He spent a 2-year internship at the Intensive Care Unit of the Florence Institute of Gerontology and Geriatrics, and was for many years Associate Professor of Biology, Human Physiology and Statistics at the University of Florence. Between 1985 and 2002 he was Chief of Geriatric Rehabilitation at the Department of Geriatric Medicine and Director of the Laboratory of Clinical Epidemiology at the Italian National Institute of Aging. During the same period, he collaborated with the NIA Laboratory of Epidemiology, Demography, and Biometry where he spent several periods as Visiting Scientist. Dr. Ferrucci has made major contributions in the design of many epidemiological studies conducted in the U.S. and in Europe, including the European Longitudinal Study on Aging, the "ICare Dicomano Study," the AKEA study of Centenarians in Sardinia and the Women's Health and Aging Study. He was also the Principal Investigator of the InCHIANTI study, a longitudinal study conducted in the Chianti Geographical area (Tuscany, Italy) looking at risk factors for mobility disability in older persons. Dr. Ferrucci is currently refining the design of the BLSA to focus more on normal aging and the development of age-associated frailty. |
| Research Interests: Aging is accompanied by a global susceptibility for a number of different diseases and functional decline that cannot be readily assessed by the currently available approaches. However, the mechanism that leads to such a susceptibility to disease and disability in the elderly is poorly understood. One possible way of gaining a better understanding of the relationship between aging, morbidity and disability is to examine such a relationship in the context of longitudinal studies. It is widely recognized that physical and cognitive function are strong predictors of mortality, independently of other traditional medical markers of poor health status. Recent data suggest that the high prevalence of comorbidity in the elderly cannot be explained by a simple stochastic process (since the incidence and prevalence of many acute and chronic diseases increases with age, older patients are more likely to be affected by multiple conditions) but rather, results from a global susceptibility to disease that specific individuals develop over the aging process. In other terms, while aging, some individuals become more "frail" than others and, as a result of this process, they are at higher risk of developing comorbidity and disability. |
| In the geriatric literature, frailty had often been defined as a state of "severe disability, typical of older persons affected by geriatric syndromes and resident in long-term care facilities." In studying frailty, we took a different approach. We conceptualized frailty as a dynamic process that becomes evident earlier in life, when specific interventions are more likely to be effective. We also hypothesized that frailty is a strong predictor of a number of negative outcomes including disability, hospitalizing, nursing home admission and mortality, and that it can be detected before any of these outcomes develop. As a first approximation, we used mobility as a proxy variable for frailty. There are intrinsic advantages in using mobility as a proxy measure for frailty. Mobility is so important to life that efficient mobility has probably been a primary target for natural selection throughout human evolution. This has led to physiologic systems that not only are highly redundant but also are capable of functioning and interacting in a number of different ways to accomplish the same task. In our studies we found that aging persons can use a number of compensatory strategies to maintain mobility even when many physiological systems are damaged. Only when this large functional reserve is exhausted, do problems in mobility emerge and can be clinically detected. We conducted a series of analyses on the longitudinal database of the EPESE study (Established Population for Epidemiological Studies of the Elderly) and found that in non-disabled older persons, poor performance in mobility and balance (performance-based tests of lower extremity function) is an independent, strong predictor of morbidity, hospital admission, incident disability, mortality and admission to a nursing home. |
| Having identified a robust proxy measure of frailty, it remained to be found why poor performance in lower extremity function is such a strong predictor of disability and other negative health outcomes. We conducted a series of studies in this direction. Taking a longitudinal perspective of the disablement process, we demonstrated that in 50% of older persons, disability results from an acute catastrophic event that, within a short period of time, leads from full function to severe disability in activities of daily living. In the other 50% of older persons, disability develops slowly and progressively and often cannot be explained by acute pathological events, at least looking at hospital admissions and discharge diagnoses over the same period. Progressive disability is more typical of the oldest old. Using data from the EPESE and the WHAS (Women's Health and Aging Study) studies, we demonstrated that high IL-6 serum level is one of the strongest, independent predictors of accelerated decline of physical function. We demonstrated that the predictive value of IL-6 on accelerated functional decline could be explained by the catabolic effect of IL-6 on muscle metabolism. Using data from the WHAS, we also found that lower extremity muscle strength is associated with walking speed only below a certain threshold of strength and that there is a synergistic effect of reduced muscular strength and balance problems in causing severe walking disability. These findings demonstrated the existence of a large functional reserve that had been intuitively proposed but never demonstrated and suggested that muscular strength is the basic mechanism for compensating for the disabling effect of balance problems. |
| Recently, in the design of the InCHIANTI study, we outlined a reference model in which the impairments that may cause mobility problems are grouped into six main subsystems: 1. Central Nervous System; 2. Peripheral Nervous System; 3. Perceptual System; 4. Muscles; 5. Bones and Joints; 6. Energy Production and Delivery. However, preliminary data suggests that the two main predictors of poor lower extremity performance are the reduction of muscle power (secondary to sarcopenia) and dysfunctions (even minor) of the central nervous system but also show that many complex interaction between the anatomical integrity and functionality of the different subsystems. A similar paradigm is currently used in the refinement of the design of the Baltimore Longitudinal Study on Aging. In particular, we plan to 1) study how the various physiological subsystems that are important for mobility interact with age in causing disability; 2) develop reference values for the integrity and functionality of the different physiologic subsystems that are implicated in mobility, to be used in clinical practice; 3) look at risk factors for the development of "soft" neurological impairments in the absence of neurological disease that is already clinically evident; 4) identify risk factors for accelerated sarcopenia and osteoporosis, including biomarkers of chronic inflammation, genetic polymorphisms and circulating levels of specific vitamins and hormones; 5) study how nutritional intake of macro- and micro-nutrients influence health status. |
| As mentioned above, our long-term objective is to unravel the biological pathways that lead to disability and comorbidity in older persons. This research topic will be examined from different perspectives that can be envisioned as superimposed layers. On the surface is the behavior in the environment that is strongly conditioned by both physical and cognitive function. However physical and cognitive performances require the integrity and functionality of multiple physiological systems, and, therefore, reduction of physical and cognitive function may result from multiple, possibly co-existing causes. Finally, loss of physiological function results from the incapacity of the organism to maintain the biological homeostasis and to provide quantity of energy compatible with the environmental requests. These mechanisms include but are not limited to inflammation, oxidative stress, autonomic nervous system, hormones and the multiple adaptative mechanisms to physical activity. The study of the effect of aging independent of diseases on these biological mechanisms and their relationship with the development of disability is the main target of the new BLSA design. |
| Recent Publications: |
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