ExperimentalGerontology,Vol. 27, pp. 567-574, 1992

0531-5565/92 $5.00 + .00 1992 Pergamon Press Ltd.

Printed in the USA. All rights reserved.

OVERVIEW OF CANCER AND AGING: A MECHANISTIC PERSPECTIVE

RONALD W. HART and ANGELO TURTURRO National Center for Toxicological Research, Jefferson, Arkansas 72079

Abstract - - Cancer and aging are approached from the standpoint of damaging agents

affectingtarget cell, local cellular environment, and the organism as a whole. The effects of exogenous agents are represented in a model emphasizing absorption, organismic disposition, and cellular disposition. Endogenous agents are represented similarly. The extent of endogenous damage is illustrated. Factors in the expression of damage as a toxic endpoint are emphasized, with the example of caloric restriction used as an example of environmental modulation of response. Key Words: cancer, aging, mechanisms, free radicals, genetic damage

INTRODUCTION IN ORDERto aid overall understanding of the complex multifocal phenomena termed cancer and aging, it is useful to consider them in the context of a cell within a local environment within the homeostatic processes of an organism. In cancer, the cell's relationship to the local environment is disturbed, leading to selective replication of a single cell. This local disturbance becomes a cancer as a result of interactions within the organism. Metastasis follows with the failure of organismic growth controls. Work using oncogenes suggests that disorder in nearly any step in the control of cellular growth can lead to cancer (Studzinski, 1989). Some oncogenes seem to effect processes similar to growth stimulatory substances, especially growth factors such as epidermal growth factor (EGF) (Travali et al., 1990). Others seem to reflect a loss of normal repression (Studzinski et al., 1990). The cancer cell's genome can be considered as a generator of a proxy local environment for the cell that simulates the embryonic one, in which the cells grow and metastasize. The mechanisms of this faux process usually involve receptor transduction processes. At the organism level, cancer cells trick the immunological system either by inducing tolerance or by simply not being immunogenic (Interagency Staff Group, 1986). When

Correspondence to: A. Turturro. 567

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the organism is immune compromised, as in AIDS, there is an increase in particular cancers (e.g., Kaposi's sarcoma). The local environment is also disrupted. One indication of this is the increase in the variance of older cell function often seen in proximate cells. One well-known example is the progressive appearance of scattered fiber atrophy in skeletal muscle (Rebeiz et aL, 1972), but it is common to many systems. It is even seen in vitro in fibroblast-like cells (Norwood and Smith, 1985). This variance disrupts the coordination of the cell and local environment, as indicated by the disruption of predominantly local phenomena, such as wound healing, by age (Kligman et aL, 1985). This disruption is better characterized at the organismic level. Better characterized is the loss in the organism's control of its cells. The loss of homeostatic control is seen in a number of physiological systems with age (Shock, 1985). The effectors of these changes are not understood, but there appears to be both a lack of response to circulatory stimulatory substances, such as seen with somatomedins, insulin-induced glucose metabolism, catecholamines, and steroid hormones (Minaker et al., 1985) (presumably as a result of postreceptor changes), and a loss of response to inhibition, as seen in the inappropriate expression of proteins (Zs-Nagy et al., 1988). One can consider, therefore, that cancer and aging at their bases are disorders in the response to growth and inhibitory substances. In a sense, cancer is inappropriate activation (or lack of inactivation) of a growth receptor response, while aging is a lack of response to those factors. When repression fails in cancer, the result is inappropriate growth. When it fails in aging, the effect is inappropriate protein, such as casein in the brain. The changes that occur in cancer seem to often involve mutation (Interagency Staff Group, 1986). In aging, one suspects that either mutation or genomic damage is involved. Damage (that may not necessarily be heritable) could alter the ability of a cell to manufacture the appropriate components for growth substance signal transduction. For these reasons, and others (Turturro and Hart, 1984), genetic damage and its effects on the cell, local environment of the cell, and the organism appear to be key to both cancer and aging. The sources of these damages are therefore vital to consider. However, an important lesson from the effects seen in induced carcinogenesis is that the conditions controlling expression can be as important as the damage itself. For instance, dioxin can be either a very potent tumor promoter or a very potent antitumor promoter, depending on conditions (DiGiovanni et aL, 1980). THE INDUCTION OF GENETIC DAMAGE Toxicant exposure Exogenous toxicants. The first event is the exposure of the organism to toxicant. This is illustrated in Fig. 1 for an exogenous toxicant. The toxicant must penetrate the interface of the environment and body (e.g., the skin surface, the intestinal mucosa, etc.) (Interagency Staff Group, 1986). It then can undergo metabolism at the entry point (e.g., skin cells) and becomes available to the circulation (blood or lymphatic). Although often ignored, these interactions can be very important for agent activity. For example, in the gut there are bacterial microflora that can result in significant reduction of agents (Cerniglia et aL, 1982). Many agents require some enzymatic activation, in which the toxicant is converted into reactive chemical species. This reactive species is often electrophilic, and can react with DNA and other cellular macromolecules (Interagency Staff Group, 1986).

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ment FIG. 1. Model of exogenous exposure. Entry portals for exposure are gut, skin, and lung. Predominant metabolism is by liver, although other organs (e.g., gall bladder, skin, etc.) can be important. Metabolites can effect target, local environment, and other organs. Excretion (dotted arrows) occurs from all sites, through entry portals.

Much of organismic metabolism is oxidative in character. Also, reduction can result in the activation of agents that otherwise would be relatively inert. The toxicant is then exposed to organismic disposition and metabolism, pharmacokinetics, which is usually accomplished by the liver, although other organs, such as skin, can approach liver activity, both in complexity and level of activity. In a process termed detoxification, the active species can react with other enzymes, which may, for example, hydroxyl N-acetylate it, or the active species may simply combine with nucleophilic scavengers. These processes are important determinants of toxicant half-life, or presence in the blood (or lymph). The toxicant, and its metabolites, can effect the target cells, the local environment of the cell, and the entire organism. When the agent enters the cells, there is cellular pharmacokinetics. Similar to that which occurs in the body, the cell controls access to the intracellular space, distributes the material among various cellular sites, and metabolizes and inactivates the agent. The cell genome is often considered the "target" of these cellular processes; however, agents can have effects on many sites, such as receptors. The agent, or its metabolites, often can adduct or combine with the DNA, leading to mutation if there is no repair of the DNA lesion.

Endogenous toxicants. Endogenous toxicants skip the first step, absorption into the body. Otherwise, they can be considered similarly as exogenous ones. Much of the load of endogenous toxicants in humans results from metabolism and temperature.

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Oxygen metabolism." The subject of a number of reviews (e.g., Floyd, 1990), the combustion process of normal oxidation generates a series of very reactive molecules. Figure 2 shows some of these, such as the superoxide radical, hydorgen peroxide, and hydroxyl free radical. The development of protective mechanisms to control the levels of these agents has been vital in evolution. Some are shown in Fig. 3. However, intense generation of either an agent or a metabolite, and close proximity of agent to the target, can result in damage. Lipid metabolism: The synthesis and degradation oflipids is critical to normal function. The production oflipids, such as occurs in prostaglandin synthesis, produces free radicals. Also, attack by a hydroxyl free radical on a lipid membrane can result in a chain propagation in which the abstraction of a proton from the target creates a free radical which can go on indefinitely. Other metabolism." The cytochrome P-450 system that is critical to the drug metabolism appears to have a major role in endogenous metabolism. There are endogenous substrates of these enzymes, such as testosterone or estrogen, that may be their major determinants (Leakey et al., 1989). Just as they produce reactive species in oxidizing exogenous agents, they can result in reactive species of their endogenous substrates. In addition, there is often a radical or reactive species in synthesis of components. For instance, S-adenosylmethionine is an important component in protein synthesis. It also damages DNA, as much as 3000 sites/cell per day (Barrows and Magee, 1982). Metals, such as iron, which are key factors in many reactions in metabolism, form complexes that are centers for the production of free radicals (Floyd, 1990). These damages are augmented by results of the biological roles that radicals have, such as use of superoxide radical by macrophages to kill bacteria. Temperature." Maintaining a cell at 37"C results in approximately 10 000 apurininc, 700 apyrimidinic, and 200 deaminated cytosine sites/cell per day, as well as over 70 000 single strand breaks in that time period (Tice and Setlow, 1985). The mechanism is spontaneous

02+

le-

superoxideradical 02 + 2 e - +

2H ÷

hydrogen peroxide

O=+3e-+3H

O~

H202

+

hydroxylradical OH" + H20= FIG. 2. Three forms of reactive oxygen. Schematic representation of the formation of superoxide radical, hydrogen peroxide, and hydroxyl radicals during oxygen metabolism.

OVERVIEWOFMECHANISMS

O~ + O~ + 2 H

571

+

Superoxide Dismutase

0

2 H=O=

~ H=O= + 02

r 2H=O

Catalase

__~

+ 1/20=

H=O= + R(OH)2 r

Peroxidase

RO 2 + H=O FIG. 3. Three enzymes limitingoxidative damage. Superoxide dismutase is the major protective system for the superoxide radical. Hydrogen peroxide is addressed by multiple enzymes, with catalase often predominant.

deamination of the bases, a process which is accelerated for methylated bases (Lindahl and Nybert, 1972). As with exogenous toxicants, endogenous toxicants are subject to organismic and cellular disposition, as well as detoxification. There is also the process of DNA repair, which can be quite efficient in certain cells for certain damages. For instance, in the case of single strand break repair, Setlow (1982) estimates that over 4 million breaks could be repaired in a day. However, damages appear to accumulate with age in cells (Tice and Setlow, 1985), which suggest that the repair is not totally effective.

Results of exposure For cancer, exogenous damage is the type of agent almost always evaluated. This is ironic since, using the United States as an example, more than half of cancer seems to be independent of any environmental effect (Doll and Peto, 1981), which suggests endogenous agents as the key factors in many cancers. For aging, the focus has been almost exclusively on endogenous damage. There are no agents that can induce aging, although a number of toxicants can induce aging-like decrements in different biological systems (e.g., radiation). Although the focus here has been on the effect on the cell genome, this is only one component in the induction of damage. In cancer, the toxicants can damage local cells, producing local cell death. Compensatory changes (i.e., reactive hyperplasia) increase local cell division. Induced cellular proliferation has been suggested as the main cause of carcinogenesis induced by a number of agents (Ames and Gold, 1990). These local effects are supplemented by the organismic effects of a toxicant. For instance, the rodent carcinogen F.D. & C. Red Dye Number 3 appears to work by inhibiting an enzyme in the pathway that signals to the hypothalamus there is sufficient T3 (Jen-

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nings et aL, 1990). This results in the hypothalamus elaborating extraneous thyrotropinstimulating hormone (TSH), resulting in thyroid tumors. In this case, the damage is to an organismic system, not a cell genome or a local environment. The effects on these three components can be seen to occur simultaneously, with either synergistic or antagonistic effects for the cancer end point. Some effects are compensatory, and others are as a direct result of damage to a specific part of some enzymatic system. In aging, since there are no "gerontogenic" compounds, what is known about the effects of damage on the cell, local environment, and organism are less clear. However, certain compounds can induce aging-like changes. The best example of this is an accidental contaminant of synthetic heroin. MPTP (1-methyl-4-phenyl-l,2,5,6-tetrahydropyridine) induces Parkinson-like symptoms in young individuals (Stern, 1990). The mechanism seems to involve neuronal cell death in the substantia nigra in the dopamine-producing cells long thought to be important for Parkinsonism. Local effects are not well characterized. However, in muscle, compensatory hypertrophy, after damage of contralateral muscle, is inhibited in older animals (Drahota and Gutman, 1962). Cancer is associated with hyperplasia and aging with hypoplasia. On the organismic level, there is a loss of circulating gonadotrophins with age (Finch and Landfield, 1985). This factor will influence the response of many systems.

EXPRESSION OF GENETIC DAMAGE As noted above, the conditions that lead to the expression of the DNA damage can be as significant as the damage itself. As long-term, complex, in vivo responses to insult, both cancer and aging can be extensively modulated by conditions. The best example of this has been demonstrated by the results found with caloric restriction (CR). CR significantly retards cancer and aging mortality. With CR, spontaneous mammary cancer is virtually eliminated at 24 months, with a similar effect on induced mammary carcinogenesis (Kritchevsky et al., 1984). Pituitary and testicular cancers are also reduced in incidence (Turturro and Hart, 1992). Aging is significantly retarded (Turturro and Hart, 1991 a). The effects of CR are many. In the context discussed above, the major effects appear to be on the organism. For spontaneous cancer, one of the most important effects is the significant decrease in circulatory gonadotropins (Merry and Holehan, 1991), presumably inhibiting hormonally sensitive cancers. For aflatoxin-induced cancer, a significant effect is the alteration of metabolism so that the agent's activation to the active species is halved (Pegram et al., 1989). This is also linked to the induced loss of gonadotropins (Leakey et al., 1991). For aging, it is not clear, but a significant effect appears to be on total metabolism and temperature (Turturro and Hart, 199 lb), again an organismic effect. The list of modulators of cancer induction are many. They include factors such as nutrition, exposure route, lifestyle, and so on. (Interagency Staff Group, 1986). Aging has not often been considered in this context; however, factors that restrict the expression of damage in carcinogenesis should also be helpful in aging. CONCLUSION Cancer and aging share many characteristics. Appreciation of the effects on cell, local environment, and the organism as a whole provides a framework to look for future direc-

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tions in aging research. By example with the mechanisms being uncovered in cancer, especially as a result of the studies of oncogene processes, some insight can be gained into mechanisms that may be of use in understanding aging.

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Overview of cancer and aging: a mechanistic perspective.

Cancer and aging are approached from the standpoint of damaging agents affecting target cell, local cellular environment, and the organism as a whole...
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