Sci. Aging Knowl. Environ., 29 June 2005
Vol. 2005, Issue 26, p. pe19
[DOI: 10.1126/sageke.2005.26.pe19]

PERSPECTIVES

Metabolomics: Opening Another Window into Aging

Bruce S. Kristal, and Yevgeniya I. Shurubor

The authors are with the Dementia Research Service of the Burke Medical Research Institute, White Plains, NY 10605, USA (B.S.K. and Y.I.S.) and the Department of Neuroscience at Weill Medical College of Cornell University, New York, NY 10021, USA (B.S.K.). E-mail: bkristal{at}burke.org (B.S.K.)

http://sageke.sciencemag.org/cgi/content/full/2005/26/pe19

Key Words: metabolome • metabolomics • metabolism • data-driven • dietary restriction • caloric restriction

Introduction

Since the time of Francis Bacon (1561-1626), the bedrock of the scientific method has been hypothesis-driven research, in which experiments are designed to test specific ideas. Over the past two decades, the advent of "-omics"-level biology--that is, studies involving the generation and analysis of very large data sets that simultaneously measure multiple variables--has begun to provide a complementary data-driven approach, with varied but increasing levels of acceptance. Metabolomics, the -omics face of biochemistry and metabolism research, is a rapidly growing field that emphasizes the simultaneous analysis of multiple low-molecular-weight metabolites from a given sample.

Metabolomics is now beginning to take its place along with the other three major -omics fields, genomics, transcriptomics (see Melov Review), and proteomics (see Gafni Perspective), each of which has previously been used to address issues in aging (see Kaeberlein Perspective and "The Big Picture"). Genomics has been most useful in tracking potential genes associated with longevity and age-related disease, but (arguably) tells us little about the aging process within individuals. Transcriptomics tells us much about how the "usage" of the genetic program can change with age (for example, in the aging brain) or under the influence of interventions that affect life span (such as caloric restriction). The utility of transcriptomics is limited, however, by its inability to reveal information about more than one tissue at a time or about posttranscriptional regulation. Proteomics has been useful for understanding the end products of the genome's transcription and for showing the accumulation of damaged products that often accompanies aging-related processes (see Gibson Perspective), but proteomics studies cannot reveal short-term regulation (except perhaps when the protein is phosphorylated). Furthermore, serum proteomics studies are limited by a series of analytical difficulties, such as the primary serum proteome being made up of very few high-abundance proteins like albumin. As noted below, metabolomics offers a complementary approach to these -omics-level technologies. Here, we propose four aging-related questions that metabolomics may be uniquely well suited to help us to address:

Metabolomics and Aging

Does aging affect metabolism qualitatively or quantitatively?

Potential linkages between aging and metabolism are broadly rooted in both lay observation and scientific discourse. These linkages are one of the few concepts that are at least broadly involved in most theories of aging, including both programmed and stochastic theories. Indeed, the broad concept that changes in metabolism both underlie and accompany aging processes was codified at least as early as 1928, in Pearl's classic The Rate of Living (1). Because metabolism is primarily controlled at the level of active biochemical inhibition and activation, proteomics and transcriptomics measurements are not expected to give much information. In contrast, measurements of metabolites, both static and in flux, will be the most efficacious means of probing metabolism.

How does aging affect the qualitative and quantitative response to pharmaceuticals and toxins?

The body's ability to respond appropriately to exogenous compounds plays a substantial role in determining the effects of that agent on the body. Decreased or altered metabolism might, for example, result in the conversion of a pharmaceutical agent into a toxicant. This topic is central to medicine in general, and its importance is magnified for members of geriatric populations who often take multiple medications. Addressing this topic is difficult because each individual is essentially unique with respect to genotype, environment, comorbidities, and pharmaceutical mix. Here, a decade of work, primarily by Nicholson and colleagues (2), has shown that it is possible to use metabolomics to trace the trajectory of shifts in metabolism associated with exogenous compounds. Observation of the path deflection within the metabolic space (analogous to changes in a planned road trip) can be used to recognize qualitative and quantitative differences between individuals in both the initial and recovery phases of pharmacokinetics and/or toxicology.

What is the relation between caloric intake/caloric balance and morbidity/mortality in humans?

Seventy years of research have firmly established dietary or caloric restriction as the most robust and reproducible known means of extending mammalian longevity and decreasing morbidity (3, 4) (see Masoro Subfield History). Decades of more recent research have shown a related effect in humans, the association of an increased body mass index (and related measures) with increases in hypertension, cardiovascular and cerebrovascular disease, diabetes, and cancer (5, 6) (see Mizuno Review). The specific relations between overnutrition/obesity and aging, morbidity, and mortality are highly controversial (see Olshansky Perspective and Tuljapurkar Perspective), with best-guess estimates of the number of excess deaths due to obesity differing by a factor of almost 10. Similarly contentious is the question of whether people who are the leanest, and thus (theoretically) the most like animals who have undergone caloric restriction, live longer and healthier or shorter and sicker lives as compared with people of average weight (7). We have identified serum biomarker profiles in rats that reflect (are indicative of) caloric restriction (8) and are in the process of adapting these profiles for use in samples of human origin, where we will attempt to answer questions of this type. Metabolomics should enable capture of the subtle shifts in interactions between nature and nurture that might otherwise be missed.

Will metabolomics lead to the development of biomarkers of aging?

The quest for biomarkers of aging has met with only minimal success (see Miller Perspective). Potential markers have been identified, but they have had little utility outside the systems in which they were developed, as well as little or no ability to make useful statements about individuals (as opposed to populations). Although there is no a priori reason to presuppose that metabolomics will be more successful than other approaches, it is noteworthy that the ability of the metabolome to most accurately reflect the most recent information about interactions between a system and its environment, and the ability of the metabolome to reflect the combined contributions of many systems (for example, urine, cerebrospinal fluid, and serum represent collection points for metabolites) offer a hope.

Conclusion

The four points raised above are, of course, only examples of the many potential opportunities that metabolomics offers to the study of aging. In general, -omics-level approaches have had four major areas of success: (i) the generation of new hypotheses; (ii) classification [particularly the use of microarrays in oncology (9)] and comparisons between models [for example, microarrays in the analysis of Huntington's disease (10)]; (iii) insights into unexpected mechanisms [for example, genomics leading to the identification of an abnormal helicase as a cause of Werner's syndrome (11)]; and (iv) cementing and filling out older knowledge. It is reasonable to expect that it is within these broad areas of knowledge that the most important benefits of metabolomics will be realized.

In closing, we note that the brevity of this position report prevents any in-depth description of the technologies and approaches being used in the field. More in-depth background may be found in the two seminal books in the field (12, 13), and a series of useful links may be found on the Metabolomics Society Web site. A new journal (Metabolomics, published by Springer) covers this field.


June 29, 2005
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Citation: B. S. Kristal, Y. I. Shurubor, Metabolomics: Opening Another Window into Aging. Sci. Aging Knowl. Environ. 2005 (26), pe19 (2005).








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