The National Institute on Aging/National Institute of Biomedical Imaging and Bioengineering: Meeting on Applications of Imaging and Sensor Technologies to Aging Research

July 22-23, 2004

Meeting Report

• Summary
• Participants
• Meeting Goals
• Agenda
  
  • General needs for new and improved measures for aging research:
    • Needs for minimally/non-intrusive, easily portable/ wearable, cost-effective devices that can be integrated into the daily lives of researchers, study participants, physicians and patients
    • Needs for new measures for animal studies
      
  • Needs for new and improved measures for specific aging-related topics:
    • Whole body energy intake and expenditure, and physical activity
    • Ovarian reserve
    • Cell death
    • Short-term fluctuations in circulating factors and hormone
    • Mitochondrial function
    • Simultaneous measurement of multiple interacting factors
      
  • Outreach Activities and Resource needs:
    • Needs for interactions and collaborations among the aging research community and the imaging and sensor research communities
    • Interactions with Professional Societies and Organizations
    • Outreach to other important scientific communities
    • Network of Research Resources
    • Training and Career Development Opportunities

Summary

The inclusion of imaging and sensor technologies in clinical aging studies can help to elucidate the physiologic processes and mechanisms of human aging and thereby provide insight into the physical and functional status of individuals in old age. The development and validation of new or improved non- or minimally invasive imaging and sensor technologies that can be applied to important clinical aging research questions requires the integration of aging, imaging and sensor research and collaboration among investigators in these research communities. The National Institute on Aging (NIA) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB) convened a meeting consisting of experts in aging, imaging, and sensor technology research to explore opportunities for collaborative research in this area, as well as future outreach and resource needs.  

Meeting Participants

The meeting participants included:

Meeting Goals

The goals of the meeting were to:

• Identify important aging-related physiologic, morphologic and/or biochemical changes for which new or better measures are needed
• Determine what existing technologies could be used to measure these aging changes; what technologies could be improved to better measure these aging changes, and what new technologies could be developed to measure these aging changes
• Explore strategies for the integration of imaging and sensor technologies into existing studies on aging

Agenda

The meeting agenda included general areas of aging research involving physiologic processes for which new or improved measures are needed. However, six specific age-related research topics were emphasized in the meeting presentations and discussions:

• Whole body energy intake and expenditure, and physical activity
• Ovarian reserve
• Cell death
• Short-term fluctuations in circulating factors and hormone
• Mitochondrial function
• Simultaneous measurement of multiple interacting factors

General needs for new and improved measures for aging research:

• Needs for minimally/non-intrusive, easily portable/ wearable, cost-effective devices that can be integrated into the daily lives of researchers, study participants, physicians and patients

 Existing measures of aging related changes and processes have several limitations. First, some instruments and technologies do not objectively measure the parameters for which they were designed. For example questionnaires often require patient self-report information on behaviors such as caloric intake, exercise and health history, most of which is subjective. Other technologies such as spirometry, and functional performance strength testing require study participant compliance with instructions and often yield missing data. On the other hand, existing large-scale technologies such as MRI, CT and PET scanning require little participation for actual data collection by study participants and patients and missing data are rare. However these methodologies are cumbersome, expensive, and require a laboratory or clinical setting. Scaled-down wearable versions of these devices would be useful and potentially less expensive if they could be produced in larger quantities. Other measures capture important properties at only a single point in time such as hormone levels, serum cholesterol, and glucose levels and are often invasive. Better understanding of the implications of the variation and rates of changes over time in these properties could be obtained from serial non- or minimally invasive measures. In some cases, no measure exists to capture important aging-related events. For example, stress response in old age is different than stress response at younger ages. Older individuals tend to react more negatively to challenges such as infections or sudden demand on cardiovascular capacity. Such responses can lead to unpredictable events such as falls or hypertensive episodes. Current technologies to capture physiologic changes that take place before such an event, what happens during the event, and what happens after the event, in real time, do not exist. While such changes could be modeled in a laboratory setting, the ability to discover physiologic events that take place in free-living individuals, such as disabilities in daily activities would be more informative and valuable.

It is therefore critical that future development of new technologies understand that human aging spans multiple organ systems within individuals. Clinical aging research focuses on the interactions of physiologic processes and underlying mechanisms within and across these systems. Thus, the development of new and improved measures for clinical aging research should take into consideration some basic properties of aging. First, aging is complex. There are likely multiple underlying factors that lead to aging outcomes. This requires the ability for serial measurements of multiple, potentially interacting and progressive aging changes that may begin very early in life and subsequently influence age-related pathologies at latter stages of life. Second, human aging is slow, with some processes taking many years (e.g., decades) to occur. Capturing very slow rates of change over long intervals requires measures that are highly sensitive. Third, aging can involve rare events, such as cell loss, and it is their cumulative effects over decades that can impact health in old age. An understanding of such events will require methodology with the ability to monitor events over time and thereby allow the identification of the pivotal point at which the accumulation leads to deleterious events.

Ideally then, the development of new and improved non- or minimally invasive technologies that would allow serial physiologic and functional measurements within an individual over an extended period of time are needed. Such measures could be used to monitor individuals in daily life, capturing natural changes as opposed to many current measures that approximate natural conditions in laboratory and clinical settings. Applications of these technologies could be used both as research tools to monitor study subjects in clinical aging studies and as diagnostic tools to manage age-related diseases and functional impairments. 

• Needs for new measures for animal studies

The development and improvement of measures of aging-related processes is also important for studies of aging in various animal models. Studies in animals offer opportunities to study basic properties of aging such as the genetic basis of longevity and the physiologic pathways that regulate the rate of aging and the onset of age-related diseases and disabilities. Also, because the life span of most animal models is much shorter than the human life span, animal studies provide the opportunity for life-long experiments and outcomes that are impractical in clinical studies because of the long human life span. Once important discoveries are made of factors that modify aging and longevity in animals (assuming these animal models are appropriate for human conditions) then such findings could translated into studies of new clinical interventions. 

It could also be the case and similar to human studies, animal studies involve many invasive measures but would benefit from the development of non-invasive in vivo measures. For example, cellular studies in mice can provide insights into stress resistance of multiple cell types. There are in vitro measures of stress resistance, but real time in vivo measures would allow for a realistic understanding of stress response in animals. Similarly, in vivo measures of T-cell response in old vs. young mice could provide insights into changes in immune function that takes place over time and potentially inform human studies on immune response to stressors in humans.  

Needs for new and improved measures for specific aging-related topics:

• Whole body energy intake and expenditure, and physical activity

In aging research, caloric restriction is known to substantially influence aging changes and increase longevity in various animal models. Yet the implications of these findings to human aging are not clearly understood because the accurate assessment of how many calories an individual takes in through eating or how many calories an individual burns remains a methodological challenge . Additionally, there are multiple factors (e.g., taste, smell, hormones, and alterations in metabolite profiles )which contribute to inter-individual differences in energy intake for which there are no measures. Studying the mechanisms of energy intake and expenditure in humans could provide insights into their role in metabolic-related processes and to the prevention or delay many age-related diseases and conditions.

Improved measures are especially needed to monitor physical activity. How much an individual moves relates to changes in energy expenditure over time. While there are current measures of physical activity, improved measures would provide incremental improvements over what already exists. Accelerometers and other physical activity monitors are cumbersome and require study subjects to remember to wear them. Smaller, wearable devices would be useful to measure movement. Additionally devices that allow measurement of movement of multiple parts of the body would be useful because different types of activities produce different types of movement and some movements are more energy expensive than others. Improved methods for determining physical activity in the minute-to-minute total energy expenditure could have a lot of use elucidating the importance of different types of food intake with physical activity.

• Ovarian reserve 

Ovarian reserve is an important indicator of female fertility potential and of the onset of menopause. Ovarian reserve decreases with age and the process of premature ovarian aging likely reflects early follicular loss and the rate of that loss. Women with premature ovarian aging have been shown to experience early menopause. Age of menopause varies among women and there is currently no reliable test of ovarian reserve to accurately remaining reproductive life-span. Currently, no perfect marker exists for ovarian reserve however Follicle Stimulating Hormone (FSH) levels under certain conditions provide some estimation. Also, researchers have developed a method using transvaginal ultrasound technology that showed a direct relationship between ovarian volume and the number of eggs remaining in the ovaries in women of reproductive age. This method uses mathematical and computer modeling to estimate the egg population decline for women entering menopause, and has the ability to predict a woman’s age of menopause. While this method can estimate ovarian reserve, obtaining and analyzing the appropriate data requires specialized expertise and thereby restricts broader use by the scientific community. The availability of an analyte or marker that could be measured easily and non-invasively at any point during a woman’s cycle that to obtain measurements of eggs, or as a surrogate, ovarian volume, or the two in combination during a given cycle would greatly facilitate this line of aging research.

• Cell death

Cell death, a discrete and rare event, occurs throughout the life span. Although individual cell loss at a given point in time may not lead to deleterious changes in tissues and organs, the cumulative effect of of cell loss over long periods of time may contribute to diseases and functional problems in old age. Understanding the mechanisms and processes that cause cell death to take place and the rates at which cell death takes place at different times across the life span could help prevent aging-related pathologies.

Currently no measures exist to capture rates and patterns of either programmed (apoptosis) or non- programmed (necrosis) cell death. Apoptotic cells maintain structural integrity until the cell dies and the cell membrane is a likely primary marker to identify apoptotic cells because dramatic changes in membrane take place during apoptosis. Necrotic cells gradually lose structure as membranes and organelles fall apart and proteins spill out into the extracellular environment. Currently, there are no identified markers for necrotic cells. There is a need for the development of in vivo measures to detect cell loss and to capture the point at which the cumulative effects of cell loss begins to deleteriously affect tissues and organs and contribute to the onset of diseases and conditions of old age.

• Short-term fluctuations in circulating factors and hormone 

Hormones and other circulating factors produce continuous rapid changes over time. Current measures that exist for some factors are obtained cross-sectionally, at one point in time, and do not capture key peaks or drops in levels at any given time. Capturing and understanding these changes could provide insights into how hormones and other circulatory factors affect changes in body composition and in the development of several age-related pathologies.

Two key hormones important to the aging process are growth hormone and cortisol. Growth hormone is produced by the pituitary gland and responsible for growth in childhood and also plays an important role in maintaining normal health in adults. It affects the development of muscle tissue, energy production, bone density and other important functions. A decline in growth hormone levels often accompanies the degenerative process associated with aging. It is possible that the restoration of growth hormone may allow maintenance of body composition similar to young adults and may improve function and allow greater independence, prevention of frailty and improved quality of life. 

Cortisol is produced by the adrenal gland that promotes the synthesis and storage of glucose. It is used in response to stress, to suppress inflammation and regulates the deposition of fat in the body. Its concentration in the blood is often used as an indicator to measure stress levels. Excessive levels of cortisol have been associated with several aging-related conditions including cancer, ulcers, diabetes, chronic pain, strokes, cardiovascular problems, Parkinson's disease, Alzheimer's disease and others.

Non- or minimally-invasive continuous measures are needed to capture the rapidly changing fluctuations in hormones and other circulating factors to better understand the factors that control secretion and the effects of the changes that take place during their circulation and their effects over the life span. The identification of gender differences would be particularly valuable. Ideally devices that could be worn constantly by individuals with the ability to transmit data to a study center or a physician’ office for analysis and monitoring would be useful to understanding the changes that take place in real-time daily lives of individuals.

• Mitochondrial function 

Mitochondria are the principal energy source within cells. As such they are crucial to the life of the cell. However, oxygen-free radicals produced by mitochondria can be damaging to the mitochondria itself and lead to mitochondrial dysfunction over time. Mitochondria from the cells of older individuals tend to be less efficient than those in the cells of younger individuals. Mutations in mitochondrial DNA have been shown to lead to several age-related diseases and have been linked to problems in cardiovascular function and in muscle metabolism. Research has shown that as mitochondria begin to dysfunction over time, they generate less ATP, are associated with exercise intolerance, and are involved in carbohydrate metabolism (insulin resistance).

Some work also suggests that mitochondria may be involved in the signaling pathway that triggers apoptosis, leading to cell loss that underlies sarcopenia (i.e., loss of skeletal muscle with age).

In human studies, muscle biopsies from human quadriceps have shown reduced quantities of mitochondria in muscle from older individuals versus muscle from younger individuals. Additionally, the energy produced from mitochondria in older individuals is reduced compared to that of younger individuals. There is a need to understand why and how mitochondrial function changes with age. New and improved measures of underlying defects in mitochondria that are responsible for the changes that occur over time are needed. Identifying the causes of deleterious changes in mitochondria over time requires and understanding of energy coupling and uncoupling between oxygen update in muscle and the ATP generated by muscle. Existing technologies using magnetic resonance and optical techniques to measure energy coupling and uncoupling are available for use in animal studies and human muscle biopsy. 

Progress has been made in the development of measures to capture qualitative (e.g., structural changes such as less ATP production per oxygen consumption or functional damage from oxidative stress) and quantitative (e.g., the amount of mitochondria that exists) mitochondrial changes over time in human and animal studies. In human muscle biopsies and in studies of mice, combination magnetic resonance and optical techniques allow simultaneous measures of oxygen uptake and ATP supply through the quantification of hemoglobin and myoglobin concentrations, two oxygen binding proteins. This approach allows a direct measure of oxygen consumption of tissue in vivo.

Existing measures of mitochondrial function allow quantitative determination of the various properties of the muscles including ATP, PCr, myoglobin and hemoglobin concentrations, all essential components of energy production in animal models and in human muscle biopsies. Techniques are needed to measure individuals in daily life with different combinations of problems with these properties. Minimal or non-invasive measures of mitochondrial function in specific tissues and properties in humans are limited. New and improved methods are needed to quantify mitochondria and identify when and how dysfunction takes place over time. In particular, measures are needed for changes in muscle properties (e.g., different patterns of fatty infiltration) in different muscles with age in different populations (e.g., active or sedentary individuals) to better understand problems in muscle function and identify interventions to help alleviate them.

• Simultaneous measurement of multiple interacting factors 

Understanding aging-related changes in physiologic function requires information on the complex interactions of multiple control systems and networks that enable an individual to adapt to the stresses of everyday life. Biologic and physiologic processes involved in these interactions cannot be truly understood when studied in isolation or at single points in time. Simultaneous measures of different processes and sequential information on multiple physiologic events can help to elucidate the mechanisms underlying the complex interactions and dynamics that occur with aging and that can contribute to a variety of aging-related conditions such as syncope, falls, and many other disorders that are not part of one organ system but that cross multiple systems. 

Much progress has been made in understanding simultaneous sequential physiologic changes that take place among multiple organ systems that lead to health outcomes in old age through the use of combined technologies. For example, several techniques have been used to understand the causes of syncope, a fainting spell usually related to temporary insufficient blood flow to the brain and a common problem in older persons that can result in falls, fractures and many other types of morbidity. Understanding what happens to the brain during syncope requires understanding of the sequence and variation of activity among multiple events that cross several organ systems at the same time (e.g., heart rate, blood pressure and respiratory dynamics).

There are several techniques that have been developed and refined to measure these dynamics. Spectral analysis has been used to look at sympathetic and parasympathetic control of the cardiovascular system and respiratory control of heart rate and blood pressure variation. Complex demodulation measures different frequencies and different amplitudes of oscillation in blood pressure in a given time series capturing low and high frequencies and plotting of different amplitudes of oscillation. A Doppler procedure is available to look at blood flow profiles in a given time series (e.g. sitting and standing) with a simultaneous measure of cerebral blood flow dynamic. MRI technology is used to measure brain blood flow and thereby brain vasomotor reactivity during changes in carbon dioxide that contribute to changes in cerebral vessels that affect blood flow. 

More imaging and sensor measures are needed to capture simultaneous and sequential changes that lead to functional problems in old age (e.g., changes in blood pressure, heart rate and cerebral blood flow that influence gait). Ideally, such measures could be scaled down in size and be worn as non- or minimally invasive devices that could captures and provide data continuously during the daily life of older individuals and provide real-time information for physicians and researchers to develop and administer appropriate interventions.  

Outreach Activities and Resource needs:

• Needs for interactions and collaborations among the aging research community and the imaging and sensor research communities

The development of the best possible measures for aging-related physiologic and functional changes requires special knowledge of aging and technology development and validation, and the development of a relationship among the aging research and imaging and sensor communities. Aging researchers and clinicians can identify the needs for new and improved measures of crucial aging-related factors. Engineers can develop appropriate technologies to measure the various physiologic and biochemical properties related to these factors. Therefore for communication and collaboration between experts in aging research and in imaging and sensor technologies are needed and encouraged to identify and develop the best measurement strategies for clinical aging studies and practice.

• Interactions with Professional Societies and Organizations

The development of special sessions or workshops at annual meetings of relevant professional societies and organizations could lead to productive information exchange and new collaborations between clinical aging researchers and the imaging and sensor research communities. For example, aging researchers could present needs for technology development at imaging and sensor professional meetings and imaging and sensor researchers could describe existing technologies that are relevant to clinical aging research at aging and other clinical professional society meetings. Additionally some clinical professional organizations and societies may have special interest groups that focus on imaging (e.g., the American College of Sports Medicine) who could take part in discussions about aging and imaging and sensor research and perhaps provide names of experts within the society who could collaborate with clinical aging researchers on applications of new and existing technologies to relevant clinical aging research.  

• Outreach to other important scientific communities

As relevant biomarkers are discovered, meetings with biotech and pharmaceutical companies to introduce the concept of healthy aging and how imaging and sensor technologies could help in testing interventions for aging-related diseases and conditions could help attract their interest and support for this research. Potentially such outreach could facilitate an opportunity to test an intervention for a disease and stimulate a field of research. One example of this type of success focused on bone research. The development of the DEXA measure stimulated this area of research and attracted industry interest in therapies for opportunity and funding that helped improve this field.

• Network of Research Resources

It would be useful to identify experts in clinical aging and other relevant biomedical research areas and bioimaging and biosensor research who could provide advice to each other on needs for new and improved technologies and who could also become potential reviewers for related projects since there are currently very few investigators with relevant joint expertise. 

Additionally, a list of biomarkers of important aging-related physiologic functions could be developed for the imaging and sensor researcher communities that would allow physicists and engineers to develop appropriate measures for capturing relevant biochemical properties needed for new and improved technologies. Also a set of specific questions that the clinical aging research community would like to explore and how the development and validation of new or improved imaging and sensor techniques could apply would be valuable to the engineering community by providing a focus on areas of research that are highly relevant aging research.

• Training and Career Development Opportunities 

Career development and other mechanisms to help train engineers in clinical aging research could help to foster collaborations across the clinical aging and engineering research communities that could lead to large productive studies over time. Additionally data output from imaging and sensor devices will need to be analyzed and the training of biostatisticians in imaging and sensor technology measures would be valuable for interpreting and publishing information from studies of clinical aging and imaging and sensor technologies.