Thomas Johnson, PhD, on the Biomarkers of Aging

"Biomarkers of aging" are a hot topic in the news--but what are they, really? Thomas Johnson, PhD, a leading expert in aging research and genetics, answered some of AFAR's questions on the subject.

Can you explain the concept of a biomarker of aging?

Yes! A “biomarker” is an easily measured trait that can be used to predict a subsequent event, such as disease. For example, blood lipid level is a biomarker that is a predictor of subsequent heart disease. Since aging is so hard to measure, it would be great if there were an easily measured trait that could be used as a biomarker of aging. For example, it would be great if we could easily ascertain whether the biological age of an individual has been changed by a drug.

Unfortunately, the only widely agreed-upon biomarker of aging is mortality rate. This is problematic for many reasons. First, mortality takes a long time to measure. Second, mortality can only be assessed on a population, not an individual. Third, mortality is only ascertained when the individual is dead.

It seems like a tiny worm with a lifespan of a couple of weeks wouldn't be able to tell us much about human longevity. How do researchers use C. elegans as a model of human aging?

It can be hard to understand how a simple species like Caenorhabditis elegans serves as a model of humans. However, this nematode worm turns out to be very informative because most of their genes are evolutionarily related to the genes humans have. This can only be understood when one remembers that all life needs to solve the same problem: how to stay alive. To stay alive, living beings need to deal with numerous, potentially overwhelming odds against survival! All life on earth stems from the same ancestor, which may have been present as early as 3 billion years ago. Multicellular life forms evolved much later-about 600 million years ago. Since something that is good for one species tends to be good for most other species, mechanisms that work tend to be conserved and passed down to offspring. There are literally thousands of examples where mechanisms, physiological traits, and genes have been maintained across the tree of life.

Since it has proven consistently difficult to unambiguously identify the specific mechanisms and processes leading to aging, it makes sense to see if one can understand aging in simpler organisms (like the nematode C. elegans). Indeed, 30 years ago the first genes that could extend life span and slow aging (using mortality as a biomarker of aging) were found by Michael Klass and myself, when we were postdocs at the University of Colorado Boulder. Thirty years later we are still looking for human genes that affect the biology of aging, and maybe we’ve found a few. In the same period of time, nematode geneticists have identified several hundred aging genes; by manipulating these genes we have been able to achieve significant increases in nematode health-span and increases of up to ten-fold in nematode lifespan. Moreover, these nematode genes are almost always similar to human genes and in many cases, understanding how the gene works in the nematode has led to better understanding of the human gene and the human gene network, at a cost that is a tiny fraction of the cost for human studies.

Are there limits to keep in mind when extrapolating from animal models in aging research to humans? What do you think are the most important ones?

There are major limitations. These include toxicology of drugs in humans that may not be toxic in model organisms and the conservation of function across species. As I said above, there are many similarities but not everything is conserved between these species. In part this is true because some of the problems an animal like the worm needs to solve to stay alive are very different from those encountered by a primate like us.

Could you sum up your research in lay terms and any promising avenues to explore?

My lab has played a principal (arguably even the major) role in establishing a genetic approach to solving the aging process of humans. We were the first to show that genetic approaches could be applied to the study of aging (1982). We proved that a single gene could lead to alterations in the biomarker of aging; we named that first gene age-1 (1988). The similar gene in humans functions in numerous ways both similar to the way it functions in the worm and in ways that are quite different. We showed that genes conveying extended life span also conveyed increased resistance to internal and external toxins. We showed that expression of one such toxin resistance protein can serve as a biomarker of aging. We have shown that there are mechanisms that “regulate” the ability to extend life and health and that these mechanisms tend to be the same across species.

We are currently identifying multiple targets in mice that can be used to slow aging in humans using pharmacological approaches. This last approach has already been incredibly informative; we have identified and have started verifying these targets through drug development.

Further Reading:

Two books describing the rise of geroscience research and targeted at non-scientists have appeared:

Anton, T., 2013. The Longevity Seekers: Science, Business and The Fountain of Youth, University of Chicago Press, Chicago, IL.

Stipp, D. 2010. The Youth Pill, Scientists at the Brink of an Anti-Aging Revolution, Penguin Group, N.Y., N.Y.10014, USA.

Papers from my lab, relevant to this discussion:

Johnson, T. E. and Wood, W. B., 1982 Genetic analysis of life-span in Caenorhabditis elegans. Proc Natl Acad Sci USA 79:6603-6607. PMCID: 347176

Johnson, T. E., Conley, W. L. and Keller, M. L., 1988 Long-lived lines of Caenorhabditis elegans can be used to establish predictive biomarkers of aging. Exp Gerontol 23:281-295.

Friedman, D. B. and Johnson, T. E., 1988 A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118:75-86. PMCID: 1203268.

Johnson, T. E., 1990 Increased life span of age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging. Science 249:908-912.

Rea, S., Wu, D., Cypser, J.R., Vaupel, J.W., and Johnson, T. E., 2005 A stress-sensitive reporter predicts longevity in isogenic populations of Caenorhabditis elegans? Nat Genet 37:894-898. PMC1479894

Johnson, T.E., 2008 Caenorhabditis elegans 2007 The premier model for the study of aging. Exp Gerontol 43:1-4. PMC:2219387.

Tissenbaum, H.A. and Johnson, T.E. 2008 Aging Processes in Caenorhabditis elegans, in Molecular Biology of Aging. Guarente, L., Partridge, L., & Wallace, D.C., (Eds) Cold Spring Harbor Press, Cold Spring Harbor, N.Y., pp.153-183.

Johnson, T.E. 2013 25 Years after age-1: Genes, Interventions and the revolution in aging research A manuscript presented as a Keynote Address at the Eleventh International Symposium on the Neurobiology and Neuroendocrinology of Ageing, Exp Gerontol 48:640-643.