Aging-Related Cell Loss in the Sleep Switch

Clifford B. Saper, M.D., Ph.D.

Harvard University, Boston, MA, Department of Neurology

Grant Program:

Clinical Neuroscience Research

Funded in:

December 2008, for 3 years

Funding Amount:


Lay Summary

Understanding How Brain Cell Loss May Relate to Sleep Deprivation in Older Adults

Investigators will determine whether sleep problems in a homogeneous group of older adults are associated with the loss of cells in a particular area of the brain.  If so, the results may lead to new methods to diminish sleep problems in adults and prevent sleep deprivation-related cognitive decline in people with dementia.

A significant proportion of older adults have problems falling asleep, staying asleep, and falling back to sleep.  They average about 45 minutes less sleep per night than younger people.  Moreover, disordered sleep is one of the major problems in people with dementing illnesses, such as Alzheimer’s disease, where sleep-wake cycles are often drastically altered.

The Harvard investigators have discovered a cell group in the brain’s hypothalamus, called the ventrolateral preoptic nucleus (VLPO), which plays a key role in producing sleep.  The investigators found that in animal models, loss of VLPO neurons results in sleep problems.  They hypothesize that loss of VLPO neurons causes sleep problems in adults as they age, and that further loss of these neurons in people who develop dementia contribute to their poor sleep and sleep-related cognitive decline.

The researchers have the opportunity to test this hypothesis in a well-characterized homogenous group of 1,000 adults—retired nuns, priests, and monks—who are participating in a longitudinal study called the “Religious Order Study” being conducted at the Rush Presbyterian St. Luke’s Medical Center in Chicago.  The participants are all cognitively healthy adults who agreed to undergo thorough neurological and cognitive exams annually, and to wear wristwatch-like activity monitors for 24 hours each year to record their sleep patterns.  Additionally, they agreed to donate their brains postmortem for autopsy, to enable scientists to correlate neurological findings during life to brain changes following death.

Based on death rates within the group to date, investigators estimate that there will be approximately 100-150 autopsy brains available to study during the grant period.  Investigators will undertake autopsy studies of the volume of VLPO neurons, and determine whether those participants who had experienced sleep problems in the two years prior to their death had decreased VLPO volumes at death compared to those without disturbed sleep.

First, they will determine whether participants’ ages were correlated with the presence and severity of sleep problems.  Second, they will determine whether the degree of VLPO neuron loss increased with age, and whether this neuronal loss directly correlated with reduced sleep duration and increasingly fragmented sleep.  Finally, they will determine whether the extent of VLPO neuronal loss and sleep problems was substantially greater in participants who developed dementia prior to their death.


Aging-Related Cell Loss in the Sleep Switch

Sleep problems are distressingly common in older individuals.  Those over 65 typically have difficulty falling asleep, have more sleep fragmentation due to frequent waking, and awaken early and cannot fall back asleep.  However, the mechanism for this sleep disruption is not known.We have discovered a cell group in the hypothalamus, the ventrolateral preoptic nucleus (VLPO), which plays a key role in producing sleep.  Loss of VLPO neurons causes difficulty in falling asleep, sleep fragmentation, and early awakening, reminiscent of sleep in older individuals.  We hypothesize that loss of VLPO neurons in older individuals may cause the sleep problems that are seen in this age group, and that further loss of VLPO neurons in degenerative dementias may contribute to the poor sleep and subsequently contribute to the cognitive deterioration in those conditions.To test this hypothesis, we will use a unique, well-characterized cohort of older individuals who are included in the Religious Orders Study (ROS) being conducted at Rush Presbyterian St. Luke’s Medical Center (RPSLMC) in Chicago.  These individuals, all retired priests and nuns, have volunteered for rigorous annual neurological and cognitive examinations, followed by brain donation and pathological examination in a rapid autopsy program at the time of their death. All of the individuals in the ROS also have annual actigraphy studies (in which they wear a wristwatch-like activity monitor for 24 hours that gives data on wake-sleep cycles). We have been offered the use of the data and pathological material from this study and will determine the degree to which individual subjects had shortened or fragmented sleep, as well as the numbers of surviving neurons in the VLPO.  This information will allow us to determine whether loss of VLPO neurons during aging is a major cause of sleep disorders in older people.

Investigator Biographies

Clifford B. Saper, M.D., Ph.D.

Clifford B. Saper received his M.D. and Ph.D. degrees and did his internship in internal medicine at Washington University School of Medicine in St. Louis, before doing a neurology residency at Cornell University Medical Center-New York Hospital.  He then joined the faculty of Washington University School of Medicine where he served from 1981-1985 as Assistant and then Associate Professor of Neurology and Anatomy and Neurobiology.  He then moved to the University of Chicago, where from 1985-1992 he was an Associate Professor, then William D. Mabie Professor of Physiology and Neurology, and Chairman of the Committee on Neurobiology.  In 1992, he moved to his present position at Harvard Medical School, where he is the James Jackson Putnam Professor of Neurology and Neuroscience and Chairman of the Harvard Department of Neurology at Beth Israel Deaconess Medical Center. Dr. Saper also has served since 1994 as the Editor-in-chief of the Journal of Comparative Neurology, the oldest basic neuroscience journal in the English language.  He also serves on the Editorial Boards of Neurology, Journal of Neuroscience, and Physiological Genomicsn.  Dr. Saper has received a Javits Neuroscience Investigator Award from the National Institutes of Health, and was named one of the 100 most frequently cited neuroscientists by the Institute for Scientific Information.  He has served as Vice President and Councilor of the American Neurological Association, and has served on the Publications Committee and has chaired the Program Committee of both that organization and the Society for Neuroscience. Dr. Saper has been named a Fellow of the American Academy of Neurology, the American Association for the Advancement of Science, and the Royal College of Physicians (London).  Dr. Saper’s research has explored circuitry of the brain that controls basic functions such as wake-sleep cycles, brain responses to immune stimulation, and the brain’s control of the cardiovascular and respiratory systems.