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.
Extending the Lifespan
Identification of the factors that affect the overall lifespan of an organism will help us better understand the aging process, and will also help us develop interventions to keep older people healthy and free of disease and/or disability as long as possible. Over the last ten years, the NIA Longevity Assurance Gene (LAG) Initiative has been pivotal in the identification of multiple genes, pathways, and biological processes involved in the regulation of longevity and aging in multiple organisms (yeast, nematode, fruit fly, mouse, human). Through the use of both invertebrate and mammalian models, the LAG Initiative has identified common factors and mechanisms that mediate longevity and extend health span.
Scientific advances in model systems provide the critical scientific foundation to extend NIA-supported studies to humans. In addition, they provide the knowledge base necessary to guide the rational development and testing of intervention strategies to delay aging, promote longevity, and extend human health span in the near future. For example, researchers recently used RNA interference (RNAi), a technique to inactivate individual genes one at a time, to identify genes involved in longevity regulation in the worm C. elegans. They found that inactivation of many genes involved in mitochondrial function extended longevity; in fact, 15 per cent of the genes influencing longevity were specific for mitochondrial function. These results reinforce the idea that energy metabolism is important in determining animal longevity.
Increased evidence of familial and genetic factors in exceptionally long and healthy life. Three recent studies of exceptionally long-lived individuals and their children suggest that a tendency for exceptionally long and healthy life to run in families may be related to exceptionally favorable risk factor profiles for cardiovascular and other diseases over the life span. In the first study, middle-aged sons of long-lived parents had lower systolic pressures, better cholesterol levels, and decreased frequencies of the APOE-e4 allele (a gene variant commonly associated with cardiovascular disease and Alzheimer’s disease) compared to middle-aged sons of shorter-lived parents. The second group found that compared to controls, children of centenarians had markedly reduced prevalence of some age-related diseases, including heart disease, hypertension, and diabetes. In the third study, researchers found that Ashkenazi Jewish centenarians and their offspring were more likely than a control group to have a variant form of a gene for a cholesterol regulating protein. This form of the gene is associated with larger-than-average cholesterol-carrying particles in the blood, and with higher levels of HDL (“good”) cholesterol, both of which were found in the centenarians’ offspring. These findings suggest that larger lipoprotein particle sizes may be one of the familial factors that promote long and healthy survival.
Together these findings add to growing evidence that the good health profiles that occur in centenarians and their children differ markedly from age-matched counterparts in the general population, and that there are familial and possibly genetic components that most likely influence protective factors against age-related disease and promote exceptionally healthy human survival. Identification of these factors earlier in life could lead to new interventions to prevent age-related diseases and disabilities, and extend healthy lifespan.
Selected Future Research Directions in the Biology of Aging
The identification of “longevity genes” is complex and necessarily interdisciplinary, involving ongoing interactions between basic and epidemiologic researchers to accelerate discovery of and confirm translational findings. To facilitate identification and understanding of longevity genes, the NIA has formed a Longevity Consortium, a self-sufficient system for rapid generation, review, and funding of new projects. Components of the Consortium include:
- Multiple basic laboratories addressing relevant disciplines including cell and molecular biology, physiology, and biochemistry
- A collaborative group of major epidemiologic studies with data on multiple outcomes in established study populations
- Diverse populations and large sample sizes to allow analyses of subgroups and covariates
- Registry and/or database capacity to allow rapid identification of possible cases and controls, and genotype and phenotype information
- Genotyping, genomics, computational, and cell line repository facilities to allow standardization and economies of scale
- System for rapid information exchange among basic and epidemiologic researchers to convey new findings and conduct follow-up studies
Members of the Consortium include epidemiologists, geneticists, population biologists, statisticians, and others with an interest in the genetic and molecular basis for longevity, and the Consortium draws on the study populations of 15 of the largest human aging studies, including the Cardiovascular Health Study, the Women’s Health Initiative, Health ABC, the Study of Osteoporotic Fractures, the Rotterdam Study, the Honolulu Heart Study, and the New England Centenarian Study. Altogether, Consortium researchers will have access to data on some 200,000 study subjects.