Aging is accompanied by gradual changes in most body systems. Research on the biology of aging focuses on understanding the cellular and molecular processes underlying these changes as well as those accompanying the onset of age-related diseases. As scientists learn more about these processes, experiments can be designed to understand when and how pathological changes begin, providing important clues toward developing interventions to prevent or treat disease. A great deal has been learned about structural and functional changes that occur in different body systems. Research has expanded our knowledge, too, of the biologic factors associated with extended longevity in humans and animal models.
Public Release of Novel Full-length Mouse cDNA Clone Collections. Arrays of DNA for specific genes permit the comparison of tens of thousands of genes at one time to determine which are turned on or off in a particular cell or condition. The NIA has assembled a collection of 7409 unique genes called the NIA mouse 7.4K cDNA clone set, which includes genes from various mouse stem cell lines, mouse early embryos, and mouse newborn organs. This set complements the existing NIA mouse 15K cDNA clone set, which has achieved international recognition as a unique and widely used resource. Like the 15K set, the 7.4K has been shipped to academic distribution centers for further replication and distribution throughout the research community. NIA scientists hope the immediate release of this additional high-quality DNA clone set to the scientific community will foster institutional collaboration and sharing of resources and speed the analysis of changes in the expression of many genes during aging processes.
A New Mouse Model of Accelerated Aging Provides Insights Into the Aging Process. NIA-supported investigators recently created a transgenic mouse carrying a mutation in the Xpd gene, which codes for an enzyme involved in both repair of DNA damage and transcription of DNA into RNA (an important first step in gene activation). This new model appears normal at birth but ages rapidly and lives only about half as long as normal mice. While not an exact model of premature aging, the new mouse model will be useful for studying a number of aspects of aging, including the roles of DNA damage and cell death, as well as the mechanisms through which the genome maintains itself and how such maintenance contributes to longevity.
Role of Telomeres in Cellular Senescence. Human cells have an inborn "counting mechanism" that tells them when to senesce, or stop dividing: Each time a cell replicates, the ends of each chromosome, called telomeres, get shorter, and once the telomeres get too short, they trigger a "senescence program" that arrests the cell's growth. Loss of telomere function can lead to genetic instability. Recent findings suggest that the senescence program is triggered by changes in the "protection state" of critically shortened telomeres, rather than their length -- in other words, the cell detects the likelihood that a shortened telomere will lead to genomic instability, regardless of the length of the telomere itself, and stops dividing as a result. Other findings suggest that the shortest telomeres in a cell become unstable and unleash the senescence program in order to avoid the propagation of genetically unstable cells.
Genetic Influences in Human Longevity. Researchers are beginning to identify biological and genetic mechanisms that might explain exceptional longevity. Using data from a study of families in which at least one member lived to be 100 or older, researchers recently found that siblings of centenarians had about half the risk of dying at every age throughout their lives compared with people who did not have a centenarian sibling, and that brothers of centenarians were at least 17 times more likely to reach the age of 100 themselves and sisters were at least 8 times more likely to live at least a century. These findings are supported by research indicating that excess longevity (the difference between observed and expected length of life) is 15 percent heritable, and that the longevity of both siblings and more distant relatives may be predictive of one's own lifespan. Together, these findings point to strong underlying genetic components of longevity and provide an approach to mapping and identifying specific genes that may play a role in determining human longevity.
New Insights Into Premature Aging Syndromes. Cockayne Syndrome-B and Werner Syndrome are devastating genetic disorders that cause accelerated and premature aging in affected individuals. The disorders are caused by mutations in the CSB and WRN genes, respectively. NIH researchers continue to elucidate the mechanisms through which the CSB and WRN genes operate, and have found that each gene is involved in DNA clean-up and repair. Recently, they found that the protein associated with the CSB gene has a role in repair of DNA damage caused by oxidative stress (cellular damage caused by molecules generated during normal energy metabolism). The protein associated with the WRN gene facilitates the activity of another protein, FEN-1, which is critical to DNA replication and repair. In fact, WRN stimulates FEN-1 more dramatically and efficiently than any other known protein. WRN also interacts with the tumor suppressor p53. The researchers conclude that mutations in the WRN gene may lead to premature aging and cancer susceptibility through dysfunction of the coordinated action of WRN protein, p53, and FEN-1 in a complex DNA repair process. These findings may suggest potential target molecules for the treatment of Werner Syndrome and Cockayne Syndrome-B, or even regulation of the aging process.
Nitric Oxide Controls the Strength of the Heart Beat. The heart is the body's most powerful muscle; its fibers stretch and contract to form the heartbeat. During periods of stress, including physical exercise, blood is pumped more rapidly throughout the body, and heart muscle stretch increases in response. Stretch also affects contraction strength; when heart muscle fibers stretch, calcium ions, which regulate contraction, are released from a part of the fiber called the sarcoplasmic reticuluum (SR). The efficiency of this process is critical to the quality of life during periods of good health, as well as during periods of disease. NIH researchers have found that heart muscle stretch activates a particular pathway that generates nitric oxide (NO). NO, in turn, enhances the fibers' capacity to release calcium ions from the SR. When the stretch is increased, as in periods of physical exertion, NO release is increased, strengthening the contraction. This mechanism could determine an important part of intrinsic cardiac reserve capacity. In addition, the researchers hypothesize that the loss of naturally occurring NO mechanisms in the body could contribute to the development of functional impairments of heart muscle when other compensatory mechanisms fail.
Extending the Lifespan
In order to understand the aging process, it is important to identify those factors that affect the overall life span of an organism. Understanding the responsible physiological mechanisms and, further, identifying ways to slow down age-related changes are important. Beyond any gains in life span, studies in this area are aimed more importantly at developing interventions to keep older people healthy and free of disease and/or disability as long as possible. Experiments in a number of animal models are providing valuable insights into the mechanisms of longevity.
A Pharmacological Intervention To Delay Aging in Fruit Flies. Using animal models, researchers are identifying possible pharmacological interventions that might be useful in delaying aging in humans. In a recent study, fruit flies fed the chemical 4-phenylbutyrate (PBA) throughout adulthood lived significantly longer than average, with no negative effects on physical activity, stress resistance, or fertility. The investigators found that two genes that became overactive in response to PBA treatment code for specific proteins that could have an impact on longevity; thus, these results also suggest a new approach in the search for genes that may play a role in longevity regulation. More research is needed to determine whether PBA treatment of other animals also affects their longevity.
The Promise of Stem Cell Research
Human pluripotent stem cells - that is, cells that are capable of dividing extensively and of giving rise to most tissues of an organism - hold enormous potential for cell replacement or tissue repair therapy in many degenerative diseases of aging. For disorders affecting the nervous system, such as AD and PD, amyotrophic lateral sclerosis, and spinal cord and brain injury, transplantation of neural cell types derived from human pluripotent stem cells offers the potential of replacing cells lost in these conditions and of recovery of function. Human pluripotent stem cells can also provide a model for studying fundamental molecular and cellular processes important in understanding aging and age-related diseases.
Another type of stem cell, multipotent or "adult" stem cells, are committed to producing cells that have a particular function. For example, stem cells circulating in the blood give rise to red blood cells, white blood cells, and platelets, but not bone cells or liver cells. Until recently, there was little evidence in mammals that multipotent cells could "change course" and produce cells of a different type. However, recent findings suggest that under certain conditions, some adult stem cells previously thought to be committed to the development of one line of specialized cells are able to develop into other types of specialized cells.
Neural stem cells are of particular interest to the study of AD and other neurodegenerative diseases of aging. Through several recent studies, we have found that environmental cues, which vary among brain subregions, may determine the fate of a stem cell, that neurogenesis may require the cooperation of multiple protein factors, and that neural stem-like cells taken from post-mortem brain tissue can form neurons. Together, these studies continue to show the potential of adult-derived neural stem cells to make different kinds of brain cells.
Adult Neural Stem Cells Make Functional Neurons. The generation of new functional neurons from neural stem cells (neurogenesis), either from those present in the brain or from those transplanted into the brain, could be harnessed to regenerate damaged brain tissue, to replace dying neurons, or to enhance the ability of the brain to respond to age-related impairments. Adult neurogenesis occurs in the hippocampus, a brain region important for learning and memory, which shows degenerative changes in aging and AD. Although the new cells resemble mature neurons, until recently it was unclear whether the new neurons are functional or integrate into existing neural circuits.
Two studies now show that neural stem cells in the adult hippocampus develop essential properties of functional neurons. In the first study, investigators labeled stem cells in the hippocampus of adult mice by tagging them with a protein called GFP. When the hippocampus was examined 2 days after the injection, the GFP-labeled cells looked like immature neurons, whereas by one month the GFP-labeled cells looked and behaved like authentic hippocampal granule neurons. Close examination showed that the new neurons had properties similar to their mature neighbors, and that they received input from other cells. In the second study, researchers isolated stem cells from the hippocampus of adult rat brain and then tagged the cells with the GFP protein. When these tagged stem cells were cultured along with normal hippocampal neurons or astrocytes, support cells that foster neuron growth, they formed neurons with axons and dendrites, which are structures critical for communication with other cells. In fact, these stem cell-derived neurons made functional connections, called synapses, with normal hippocampal neurons and with each other, and released neurotransmitters, the chemical mediators of neuronal communication.
Isolation of Neuron-Restricted Precursor Cells from Human Embryonic Stem Cells. Cells in the brain and central nervous system differentiate through a multi-step process. As development progresses, stem cells - cells with a unique capacity to regenerate and give rise to many tissue types - generate a class of cells known as precursors or progenitors, which in turn generate the highly specialized cells of the brain and nervous system. Scientists now have the ability to isolate human embryonic stem (hES) cells, and have found that hES cells proliferate and maintain their pluripotency (ability to give rise to different tissue types) in cell culture.5 NIH researchers have recently developed a method for inducing hES cells to differentiate into neural progenitor cells and neurons. The newly-derived cells exhibit the appearance and properties of cells ordinarily found in the brain and central nervous system. These data indicate that hES cells could provide a source for neural progenitor cells and mature neurons for therapeutic and toxicological uses.
Selected Future Research Directions in the Biology of Aging
The Aging Intervention Testing Program. In 2002, the NIA issued a Request for Applications (RFA) for the Aging Intervention Testing Program, a large-scale initiative to test potential intervention strategies that may slow the rate of aging in animal models. It is anticipated that positive results could be followed up with clinical trials to establish safety and efficacy in humans. A secondary goal is to identify interventions that are not safe or are not effective; such knowledge would be highly relevant in assessing appropriate candidates for clinical trials.
- Carpenter, MK et al. Enrichment of Neurons and Neural Precursors from Human Embryonic Stem Cells. Exp. Neurol. 172: 383-397, 2001