REJUVENATION RESEARCHVolume 9, Number 2, 2006© Mary Ann Liebert, Inc.

Negligible Senescence: How Will We Know It When We See It?

CHRISTOPHER B. HEWARD

ABSTRACT

The recent public claim that “SENS is a practical, foreseeable approach to curing aging” hasstirred considerable controversy among bio-gerontologists. Testing this hypothesis will notonly require precise definitions for the somewhat subjective terms “practical,” “foreseeable,”and “curing,” it will require a precise definition of the term “aging.” To facilitate proper ex-perimental design, this definition must focus on the nature of aging itself, not its causes orconsequences. Aging in mammals is a process that begins early in adult life and continuessteadily thereafter until death. It is manifested by a decline in the functional capacity (or,more precisely, reserve capacity) of a variety of vital physiologic systems leading to increas-ing risk of morbidity and mortality over time. Aging, however, cannot be measured by sim-ply monitoring morbidity and/or mortality. Aging can only be measured by monitoring thedecline of global functional capacity itself. This, in turn, will require an operational defini-tion of aging expressed as a rate function (i.e., it will have units expressing aging as an over-all rate of functional change per unit time). Widespread acceptance of such global indexes ofaging rate in animal models and humans will greatly facilitate research activity specificallydesigned to increase the understanding of aging mechanisms and antiaging interventions.

INTRODUCTION

WHEN IN WAS FIRST PROPOSED in 2002, theidea of developing “strategies for engi-

neered negligible senescence” (SENS) was ex-tremely controversial. It still is.1 Many bio-gerontologists are skeptical that the approachwill result in a “cure” for aging anytime soon.However, there is increasing optimism amongscientists that interventions, for the purpose ofcombating human aging and its consequences,will be developed within the foreseeable fu-ture. If and when such interventions becomeavailable (after having been validated in ani-mal models such as nematodes, Drosophila,and mice), a way must be found to determine

their safety and efficacy in human beings. Timeand expense considerations obviously precludehuman survival studies for this purpose.Therefore, an alternative approach is needed.

Stated briefly, the basic idea behind SENS isthat senescence (aging) is a function of only“seven deadly things” that occur as intermedi-ate steps between the metabolic determinantsof aging and their pathologic consequences.2Although the metabolic mechanisms andpathologic consequences of aging are exceed-ingly difficult to understand and conquer, ag-ing may be curable if these seven types of cel-lular and tissue damage can be cured.Specifically, they include: (a) cell loss, or atro-phy; (b) nuclear mutations and epimutations;

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(c) mitochondrial DNA mutations; (d) senes-cent cells; (e) protein crosslinks; (f) extracellu-lar junk; and (g) lysosomal junk.

Testing this hypothesis will be extremely dif-ficult because there is no current consensusabout what constitutes aging or how best tomeasure it. If agreement cannot be reached thenature of aging itself, how can one hope toagree on the best method for measuring it? Oneapproach to testing antiaging interventions, thesurvival study, has been used for years in ag-ing research. It is based on the notion that anintervention capable of increasing the maxi-mum lifespan of a species must be doing so byslowing aging. However, there is a flaw in thislogic. Although it is true that slowing is verylikely to increase maximum lifespan, it does notnecessarily follow that an increase in maximumlifespan indicates that aging has been slowed.Theoretically, many things could result in in-creased longevity (increased maximum lifespan)without influencing aging rate (e.g., prolongeddevelopment, reduction of environmental haz-ards, and reduced disease risk).

Human centenarians usually die from a de-generative disease or cancer. Presumably anyintervention capable of preventing cancer orslowing the progression of degenerative dis-eases could increase human maximum lifespanwithout influencing aging rate at all. Nonethe-less, the scientific community has widelyadopted the survival curve as a way of mea-suring the efficacy of antiaging interventions.This has led to rampant misuse of survivalstudies and misinterpretation of mortality datain the study of aging. In particular, life ex-pectancy and maximum lifespan have been ac-cepted as indirect measures of aging. In reality,such data say nothing about aging rate in in-dividual organisms. They describe only thedeath rates of populations.3 The death rate maybe a useful “biomarker” of aging in populationstudies, but it is certainly not the only one. Amore detailed analysis of the shortcomings ofsurvival curves is beyond the scope of this dis-cussion, but will be provided elsewhere (man-uscript in preparation). Suffice it to say thatwhat is needed is a more direct way to studyaging.

Perhaps bio-gerontologists should follow theexample of endocrinologists in their approach

to research. The field of endocrinology has beentremendously successful in advancing the un-derstanding of hormones and their role in hu-man health and disease. This success has comebecause endocrinologists followed six sequen-tial steps along the pathway to discovery: defi-nition, identification, measurement, understand-ing, manipulation, and therapeutics.

Endocrinologists wasted little time debatingfundamental theoretical issues such as, “Whatis a hormone?” They realized early on that thisquestion cannot be answered by doing experi-ments. It is not an empiric question to be an-swered by discovery. It is a conceptual questionto be answered by consensus. Endocrinologistscould not go out in the world to discover hor-mones until they had first defined what it wasto be a hormone. Once they reached a consen-sus about the essential characteristics of hor-mones, they set about identifying moleculesthat satisfied their definition. Then, they beganto develop techniques for measuring those hor-mones so they could properly study them. Ex-periments using these measuring methods ledto greater understanding of endocrine systemsand their interactions. From this knowledge,their ability to manipulate and control thesesystems quickly followed. Perfection of suchtechnologies has resulted in the developmentof a wide variety of therapeutic interventions.Thus, clinical endocrinologists are now able totreat hormone deficiencies or excesses thatmanifest themselves as clinical diseases and inso doing, help people live longer, with a higherquality of life.

Applying the preceding six steps to geron-tology may facilitate the development of ther-apeutic interventions that will significantlyslow the rate of aging and increase healthy hu-man lifespan. The first step in this process willbe to arrive at a general consensus on the def-inition of aging. As with the question, “Whatis a hormone?” the question, “What is aging?”cannot be answered empirically. It must be de-fined operationally to serve a specific purpose.This approach must be applied on a species byspecies basis, because aging manifests differ-ently in different species.

How this approach might be applied to hu-mans is shown in Figure 1. Aging is illustratedas a sloping line depicting a progressive, de-

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generative decline in global functional capac-ity over time. This provides a very useful wayto measure aging rate quantitatively, in bothgroups and individuals. Once this definitionhas been accepted, the next step is to identifybiomarkers of aging that satisfy the require-ments implied by this definition. Thus, anymeasurable parameter that reflects a decline inphysiologic or biochemical function within asingle individual over time is a potential can-didate. Cross-sectional and longitudinal stud-ies of such biomarkers will result in data thatcan be expressed as a line with a specific slope.Normative cross-sectional and longitudinaldata from the same study population will havethe same slope (aging rate). Of course, indi-vidual subjects within the population will havedifferent slopes.

One advantage of using biomarkers to studyaging is that it focuses attention on the agingprocess itself, not its final outcome. Aging ismeasured as a rate function, with units ex-pressed as a change in the measured biomarkerper unit time. In this paradigm, if one is nottalking about rates of change, then one is nottalking about aging. Furthermore, defining ag-ing in this way virtually eliminates confusionabout the difference between aging and devel-opment. Although it may be argued that peo-ple below the age 20 are aging, this is not thesort of aging in which most bio-gerontologistsare interested. The developmental biology ofyoung people (�20) is another field entirely.Choosing biomarkers based upon an opera-tional definition of aging focuses bio-gerontol-ogists on the study of adult aging.

Of course, the idea of using biomarkers tostudy aging is not new. The Baltimore Longi-tudinal Study on Aging (BLSA) began in 1958and continues to this day. In addition, the Na-tional Institute on Aging has sponsored a num-ber of workshops over the years to generate in-terest in biomarker research, but results havebeen disappointing.4 Although many promis-ing biomarkers of aging have been identified,no universally accepted global index of aginghas been established.

The reason for this apparent failure is notthat good candidate biomarkers could not befound. The effort failed because validation cri-teria were conceptually flawed, unrealistic, andbased upon a number of false assumptions. Forexample, the ideal of deriving from a multi-variate equation an index of “biologic age” thatperfectly predicts an individual’s chronologicage makes no sense and is counterproductive.Such an index would now be of practical value.Likewise, it is of little value to compare healthysubjects to unhealthy subjects or at-risk groups(e.g., smokers) to validate a biomarker. Nor isit appropriate to test the validity of a biomarkerusing caloric restriction (CR), based upon theassumption that CR slows aging. This, obvi-ously, begs the question and ignores increasingdoubt among bio-gerontologists that CR slowsaging.5 Finally, validation criteria requiringthat candidate biomarkers forecast lifespanwere too stringent, underestimating the im-portance of other factors, unrelated to aging, indetermining longevity.

There are, in fact, a great many promisingcandidate biomarkers of aging, at least in hu-mans. Table 1 lists just some of the many typesof biomarkers that have been identified andpartially validated in literature. These repre-sent the breadth and depth of biomarkers thatmight be used to create a global index of func-tional capacity. The BLSA itself has generatedlongitudinal data on a number of physiologicand biochemical parameters, many of whichmay serve as components of such an index. Ingeneral, functional capacity, as measured by abattery of selected biomarkers, peaks in theearly twenties and declines more or less lin-early thereafter (see Fig. 1).

This approach to the study of human agingis widely accepted by bio-gerontologists. All

FIG. 1. Aging and anti-aging, operationally defined.

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that is needed is a consensus about which bio-markers to include in developing a global in-dex of aging. This has been attempted for hu-mans many times in the past with some degreeof success.6 Obviously, identification of differ-ent sets of biomarkers would be required fordifferent organisms. However, once a set ofbiomarkers has been accepted and an “agingindex” established for a given organism, re-searchers would have very useful tools forstudying aging. Such tools would then be usedfor experimentation (analogous to that de-scribed in the preceding in endocrinology) de-signed to further the understanding of funda-mental aging mechanisms and their control.Perhaps more importantly, such tools providea means for evaluating interventions that havethe potential for modifying the trajectory of de-cline, even though the mechanisms may not beunderstood.

Putative anti-aging interventions have beenproposed for thousands of years. Most of thesehave been proposed by witch doctors and char-latans, however, in recent years, scientists havebegun to seriously consider other possibilities.These include: CR and CR mimetics, antioxi-dants, hormone replacement therapy, AGEbreakers, insulin and IGF pathway modulators,stem cell therapy, telomerase inducers, thera-peutic cloning, genetic engineering, and more.The list goes on and on, especially the furtherone looks into the future. It seems almost in-evitable that, within the foreseeable future, oneor more interventions will be discovered thatwill significantly reduce the rate of aging in

mice. Currently, there is no way of testing thesafety and efficacy of such interventions in ahuman population.

Survival studies are not practical in humansand many of the invasive techniques often usedin animal studies are not allowed in human re-search. How then will promising anti-aging in-terventions (e.g., SENS) be tested in humans?First, anti-aging interventions must be devel-oped that successfully slow the aging rate asdescribed. Confirmation of this will include us-ing survival studies to show prolongation ofmean and maximum lifespan in short-livedmammals. When the appropriate animal vali-dation studies have been completed, the onlyway to test the safety and efficacy of such in-terventions in a human population is in themanner described in the preceding. A popula-tion of healthy subjects on whom a global in-dex of aging has been measured longitudinallyfor many years would be the ideal study group.As shown in Figure 1, subgroups of this pop-ulation exposed to genuine anti-aging inter-ventions would be expected to exhibit a changein their rate of aging as indicated by a changein the slope of their Global Functional Capac-ity (GFC) curve. Depending upon the accuracyand precision of the GFC index, if the reduc-tion in aging rate is great enough, the effect ofsuch interventions will be measurable within arelatively short period of time (5 to 10 years).

In the future, after a global index of aginghas been established for a large human popu-lation and its validity widely accepted, experi-ments involving the direct measurement of ag-

TABLE 1. A NUMBER OF PROMISING CANIDATE BIOMARKERS FOR THE STUDY OF HUMAN AGING

Physiologic biomarkers Biochemical biomarkers

Pulmonary function tests Renal function tests (GFR)Cognitive function tests Liver function testsSensory acuity tests Telomere fragment lengthStatic balance/postural sway Free radical damage testsBasal metabolic rate Advanced glycation end productsBone mineral density DHEA-SO4Muscle strength and endurance InsulinBody composition Insulin-like growth factor-1Flexibility and elasticity Sex hormones and binding proteins

These are just a few of a great many such candidate biomarkers that have been suggested over the years. Althoughsome biomarkers may be useful for measuring aging in different closely related species, it is likely that a largelyunique set of biomarkers will be required in distantly related species.

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ing, expressed as a rate function (change inGFC per unit time) will become commonplace.Such studies will bring the day closer when onecan truly test SENS and answer the question,Negligible senescence: How will we know itwhen we see it?

REFERENCES

1. de Grey ADNJ, Baynes JW, Andersen JK, Bartke A,Campisi J, Heward CB, McCarter RKM, Stock G. Timeto talk SENS: critiquing the immutability of human ag-ing. Ann NY Acad Sci 2002;959:452–462.

2. de Grey ADNJ, Baynes JW, Berd D, Heward CB, Paw-elec G, Stock G. Is human aging still mysteriousenough to be left only to scientists? BioEssays 2002;24(7):667–676.

3. Gompertz B. On the nature of the function expressiveof the law of human mortality and on a new mode of

determining the value of life contingencies. PhilosTrans Roy Soc London 1825;115:513–585.

4. Sprott RL. Biomarkers of Aging. J Gerontol 1999;54A:B464–465.

5. Mair W, Coymer P, Pletcher SD, Partridge L. Demog-raphy of dietary restriction and death in Drosophila.Science 2003;301:1731–1733.

6. Balin AK, ed. Practical Handbook of Human BiologicAge Determination. Boca Raton, FL: CRC Press, 1994.

Address reprint requests to:Christopher B. Heward, Ph.D.

Kronos Science Laboratories, Inc.2222 E. Highland Avenue, Suite 220

Phoenix, AZ 85016

E-mail: chris.heward@kronoslaboratory.com

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