Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Biochemical Basis of Aging David E. Green To cite this article: David E. Green (1975) Biochemical Basis of Aging, Postgraduate Medicine, 57:3, 147-152, DOI: 10.1080/00325481.1975.11713993 To link to this article: http://dx.doi.org/10.1080/00325481.1975.11713993
Published online: 07 Jul 2016.
Submit your article to this journal
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Date: 26 August 2017, At: 18:01
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All complex molecules of the kind dealt with in biologic systems have prescribed lifetimes by virtue of the intense turbulence to which they are continuously subjected. This aspect of aging, which may be called aging at the molecular level, places a ceiling on longevity.
FAMILY PRACTICE AND
BIOCHEMICAL BASIS OF AGING
Aging of the whole organism is an expression of aging at the cellular and molecular level. We may think of cells as composites of systems concerned with energy, heredity, and control; the structural materials such as collagen and hyaluronic acid could be considered as supportive of one or another of these three basic systems. All these subcellular systems undergo the aging process, and the cause of aging is similar, if not identical, in all cases. We may therefore concentrate on only one of the cellular systems -the energy system-without running a serious risk of missing the nub of the problem.
DAVID E. GREEN, PhD University of Wisconsin Madison
This is the first in a series of articles adapted from a course in problem solving in clinical geriatrics presented by the University of Wisconsin Center for Health Sciences, Madison. Dr. Sigurd E. Sivertson was chairman of the conference. Dr. Sture A. M. Johnson is coordinator of the series.
The Enzymes
The most fundamental units of energy manipulation in cellular systems are the enzymes, the protein .molecules that catalyze one of the thousand or more chemical reactions intrinsic to metabolism. In theory, an enzyme should not be used up in the course of carrying out its catalysis. That is true, but the enzyme, like all protein molecules, is vibrating in solution a million times per second by virtue of thermal agitation, continuously colliding with a variety of other molecules and ions. In other words,
Vol. 57 • No. 3 • March 1975 • POSTGRADUATE MEDICINE
147
........................................................................................ ·····~············································································ ..... . The mitochondrion, like the enzyme,
The Mitochondrion
cannot replicate itself. When it .. dies, it must be replaced by new ·· Downloaded by [Australian Catholic University] at 18:01 26 August 2017
mitochondria generated de novo by .. the hereditary apparatus of the cell.
..
enzymes are subjected to intense molecular turbulence. Perhaps once in a billion turnovers of a particular enzyme molecule can an unusually energetic collision lead to a chemical alteration. Some group in the enzyme may become oxidized or in some fashion altered. With this alteration the enzyme molecule becomes less stable and more susceptible to further alteration; finally it becomes altered to the point that it completely loses its catalytic function. The cell treats an inactivated enzyme as a foreign protein, which is eliminated by the appropriate mechanisms. This fate i~ not peculiar to only a few enzymes-it is true of all enzymes. They have a limited life span-days, weeks, or months-which is different for different enzymes, but all enzymes and, for that matter, all proteins are "mortal" and their life span as functional entities is narrowly circumscribed. 1 The daily vitamin requirements provide the most direct evidence of the vulnerability of enzymes. Vitamins generate the prosthetic groups of a large number of enzymes. 1 From the minimum daily requirements for vitamins we can deduce exactly how long certain enzymes survive in the animal body. The survival time varies for the different enzymes, but on the average, it is not long-a matter of months. As old enzyme molecules deteriorate and become eliminated, new replacement molecules of the same enzyme are formed, and thus, a balance always exists between the process of aging
148
and decay and the process of replication and replacement. When this balance is disturbed, as in vitamin deficiency, an organismic crisis is inevitable.
Each cell has organelles, such as the mitochondrion, the cell membrane, the nucleus, the Golgi apparatus, etc. As a broad generalization, we may think of these organelles (usually membrane systems) as the instruments of energy coupling. 2 One organelle in particular, the mitochondrion, is the seat of adenosine triphosphate production and is the energy-coupling system par excellence. One mitochondrion may contain as many as several million molecules of enzymes, most of which are mounted within membranes. A mitochondrion is just as vulnerable as a single enzyme molecule. It has a limited lifetime-a matter of several weeks at most. Fletcher and Sanadi3 have used radioactive labels to determine the lifetime of liver mitochondria. When mitochondria age and their function deteriorates, they invariably swell, critical eoenzymes leak out of the interior, the mechanisms which control the configurational state become inoperative, and finally, the membranes enveloping the mitochondrion perforate and the internal contents are extruded into the cytoplasm of the cell. 4 Probably much the same kind of disruptive molecular catastrophe befalls the mitochondrion as befalls the individual enzyme. The catastrophe is infrequent, but the probability is high that within a certain time period the catastrophe will take place with the inevitable end point of mitochondrial "death." The mitochondrion, like the enzyme, cannot replicate itself. When it dies, it must be replaced by new mitochondria generated de novo by the hereditary apparatus of the cell. The one difference between the mitochondrion and the enzyme is that the mitochondrion has a control mechanism which can regulate, within narrow limits, the response of the mitochondrion to changes in external conditions. This control mechanism, however, is no protection against
POSTGRADUATE MEDICINE • March 1975 • Vol. 57 • No. 3
the inevitable molecular catastrophe to which all mitochondria and all organelles are susceptible with predictable frequency. 5
Downloaded by [Australian Catholic University] at 18:01 26 August 2017
The Aging Process
Aging, whether of the mitochondrion or of an enzyme, is a consequence of destructive molecular collisions leading to chemical modification of proteins and loss of catalytic function. As far as we know, there is no way of preventing or eliminating such molecular catastrophes. They are intrinsic to the physical world of molecules. All complex molecules of the kind dealt with in biologic systems have prescribed lifetimes by virtue of the intense turbulence to which they are continuously subjected. This aspect of aging, which may be called aging at the molecular level, places a ceiling on longevity. The complex molecules of living systems, be they of the energy, heredity, or control systems, are vulnerable molecules and must be continuously replaceable. The replacement systems are not exempt from this disability. These too contain complex molecules which are vulnerable to molecular catastrophe. There is in the end no way around the inevitable aging and deterioration of specialized multicellular organisms. Aging in a cell is at a higher level of organization. The mammalian red blood cell, which lacks the hereditary equipment for replacement of any of the cellular constituents, is a good example for consideration. This allows us to focus on cell aging without becoming enmeshed in the problem of replacement. The lifetime of a mammalian red blood cell is determined by the stability of its membranes and complex molecules and by the frequency with which these molecules undergo catastrophic inactivation. The red blood cell has basically one organelle, namely, the plasma membrane, and the cell lasts as long as the membrane is intact. The mammalian red blood cell lasts an average of 100 days, give or take a few days. 6 When a red blood cell fails, it leaks hemoglobin, undergoes change from its normal biconcave discoid shape to a sphere, and finally perforates into disorganized fragments. Again, the cause of this cell
Vol. 57 • No. 3 • March 1975 • POSTGRADUATE MEDICINE
DAVID E. GREEN
Dr. Green is in the Institute for Enzyme Research, University of Wisconsin, Madison.
death can be attributed to the inevitable molecular catastrophe which befalls the protein molecules in the plasma membrane. When a sufficient number of such catastrophes have taken place, the stability and function of the plasma membrane become attenuated to the point that the membrane can no longer contain hemoglobin and it ruptures, with loss of cell contents. The red blood cell is an expendable cell, and therefore its aging process is by no means typical of other cells such as cardiac or nerve cells, which have a high degree of built-in replacement capability. Every part which is worn out is, in principle, replaceable, be this part in the cell membrane, the mitochondrion, the sarcoplasmic reticulum, or the actomyosin. In such a cell, the inevitable aging which results from molecular catastrophes is balanced by what may be called replacement therapy. The damaged sector is replaced by an undamaged, newly generated sector. How this replacement is done is still not known, but at least we know that it must go on because cells like cardiac cells and nerve cells can survive as long as the lifetime of the organism. In a sense, the nonexpendable cells "outwit" the aging process by the tactic of continuous replacement. This tactic is insufficient when the cell suffers acute trauma as in a myocardial infarct and the rapidly sustained damage is too extensive to be rectified in time. Under such (Continued on page 152)
149
Problems of Aging
........................................................................................... .... ............ ... ... ..... ...... .... .... ... ... ...... .. .... ... .. .... .. ..... ... ... ... ...... .
When the replacement therapy begins to fail, cell death becomes inevitable. With each irreplaceable cell that dies, Downloaded by [Australian Catholic University] at 18:01 26 August 2017
organ function is diminished, and finally, organismic function is threatened. circumstances, neither the protective control mechanisms nor the replacement therapy can intervene before irreversible changes set in and cell death results. The tactic of replacement therapy is also insufficient when the replicating systems that generate the replacement parts undergo aging and can no longer produce with fidelity the parts to be used in replacement. The picture that finally emerges from this consideration of the component elements in the aging process at the molecular level is that aging is a consequence of the stepwise shift in the balance between the inevitable molecular process of deterioration and loss of function and the replacement of damaged proteins and damaged organelles within individual cells. At the point that the replacement therapy begins to fail, cell death becomes inevitable. With each irreplaceable cell that dies, organ function is diminished, and finally, organismic function is threatened. The chain of causality from the molecular event at the level of enzymes to the integrated behavior of the whole animal is then complete. The consequences of the aging process are different, depending on the cell. The aging of a hair follicle is clearly less serious than the aging of a nerve cell. Both may be irreplaceable, but the loss of the former does not affect the performance of the organism, whereas the loss of the latter is potentially catastrophic as the process of cell death builds up. All this leads up to the notion that the aging process, though uni-
152
versa! in all types of cells, assumes overriding importance in cells of the critical organs-the heart, the nervous system, the brain. If we are to make progress in the tactics for slowing up or arresting the aging process in man, we must fully comprehend the cellular technology for replacement of damaged components such as enzymes, organelles, and membranes. It is the preservation of this technology in the cells of critical organs that is the first line of defense against the aging process. Conclusion
Among the remarkable achievements of molecular biology is the discovery of the control mechanisms which regulate the repair of breaks in nucleic acid arising from chance molecular catastrophes. 7 Here is direct evidence of the operation of one of the intrinsic cellular techniques for repairing the ravages of molecular catastrophes. This is only one component of the replacement therapy technology. What is distressing is the state of our ignorance about the biochemical basis of this technology. The problem of aging at long last can be defined with some precision. The blueprint for the design of meaningful research programs for the study of aging in man can now be constructed. Address reprint requests to David E. Green, PhD, lnsti· tute for Enzyme Research, University of Wisconsin, 1710 University Ave, Madison, WI 53706. REFERENCES 1. Green DE, Goldberger RF: Molecular lnsights Into
2. 3. 4. 5. 6. 7.
the Living Process. New York, Academic Press, lnc, 1967 Green DE, Baum H: Energy and the Mitochondrion. New York, AcademiC Press, lnc, 1970 Fletcher MJ, Sanadi DR: Turnover of liver mitochondrial components in adult and senescent rats. ] Gerontal 16:255, 1961 Lehninger AL: The Mitochondrion. Menlo Park, Calif, WA Benjamin, Inc, 1964 Southard J, Nitisewojo P, Green DE: Mercurial toxicity and the perturbation of the mitochondrial control system. Fed Proc 33:2147-2153, 1974 Bishop C, Surgenor DM (Editors) : The Red Blood Cell. New York, Academic Press, Inc, 1964 Lehman IR: DNA ligase: Structure, mechanism, and funaion. Science 186:790·797, 1974
POSTGRADUATE MEDICINE • March 1975 • Vol. 57 • No. 3
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Biochemical Basis of Aging David E. Green To cite this article: David E. Green (1975) Biochemical Basis of Aging, Postgraduate Medicine, 57:3, 147-152, DOI: 10.1080/00325481.1975.11713993 To link to this article: http://dx.doi.org/10.1080/00325481.1975.11713993
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Australian Catholic University]
Date: 26 August 2017, At: 18:01
Downloaded by [Australian Catholic University] at 18:01 26 August 2017
All complex molecules of the kind dealt with in biologic systems have prescribed lifetimes by virtue of the intense turbulence to which they are continuously subjected. This aspect of aging, which may be called aging at the molecular level, places a ceiling on longevity.
FAMILY PRACTICE AND
BIOCHEMICAL BASIS OF AGING
Aging of the whole organism is an expression of aging at the cellular and molecular level. We may think of cells as composites of systems concerned with energy, heredity, and control; the structural materials such as collagen and hyaluronic acid could be considered as supportive of one or another of these three basic systems. All these subcellular systems undergo the aging process, and the cause of aging is similar, if not identical, in all cases. We may therefore concentrate on only one of the cellular systems -the energy system-without running a serious risk of missing the nub of the problem.
DAVID E. GREEN, PhD University of Wisconsin Madison
This is the first in a series of articles adapted from a course in problem solving in clinical geriatrics presented by the University of Wisconsin Center for Health Sciences, Madison. Dr. Sigurd E. Sivertson was chairman of the conference. Dr. Sture A. M. Johnson is coordinator of the series.
The Enzymes
The most fundamental units of energy manipulation in cellular systems are the enzymes, the protein .molecules that catalyze one of the thousand or more chemical reactions intrinsic to metabolism. In theory, an enzyme should not be used up in the course of carrying out its catalysis. That is true, but the enzyme, like all protein molecules, is vibrating in solution a million times per second by virtue of thermal agitation, continuously colliding with a variety of other molecules and ions. In other words,
Vol. 57 • No. 3 • March 1975 • POSTGRADUATE MEDICINE
147
........................................................................................ ·····~············································································ ..... . The mitochondrion, like the enzyme,
The Mitochondrion
cannot replicate itself. When it .. dies, it must be replaced by new ·· Downloaded by [Australian Catholic University] at 18:01 26 August 2017
mitochondria generated de novo by .. the hereditary apparatus of the cell.
..
enzymes are subjected to intense molecular turbulence. Perhaps once in a billion turnovers of a particular enzyme molecule can an unusually energetic collision lead to a chemical alteration. Some group in the enzyme may become oxidized or in some fashion altered. With this alteration the enzyme molecule becomes less stable and more susceptible to further alteration; finally it becomes altered to the point that it completely loses its catalytic function. The cell treats an inactivated enzyme as a foreign protein, which is eliminated by the appropriate mechanisms. This fate i~ not peculiar to only a few enzymes-it is true of all enzymes. They have a limited life span-days, weeks, or months-which is different for different enzymes, but all enzymes and, for that matter, all proteins are "mortal" and their life span as functional entities is narrowly circumscribed. 1 The daily vitamin requirements provide the most direct evidence of the vulnerability of enzymes. Vitamins generate the prosthetic groups of a large number of enzymes. 1 From the minimum daily requirements for vitamins we can deduce exactly how long certain enzymes survive in the animal body. The survival time varies for the different enzymes, but on the average, it is not long-a matter of months. As old enzyme molecules deteriorate and become eliminated, new replacement molecules of the same enzyme are formed, and thus, a balance always exists between the process of aging
148
and decay and the process of replication and replacement. When this balance is disturbed, as in vitamin deficiency, an organismic crisis is inevitable.
Each cell has organelles, such as the mitochondrion, the cell membrane, the nucleus, the Golgi apparatus, etc. As a broad generalization, we may think of these organelles (usually membrane systems) as the instruments of energy coupling. 2 One organelle in particular, the mitochondrion, is the seat of adenosine triphosphate production and is the energy-coupling system par excellence. One mitochondrion may contain as many as several million molecules of enzymes, most of which are mounted within membranes. A mitochondrion is just as vulnerable as a single enzyme molecule. It has a limited lifetime-a matter of several weeks at most. Fletcher and Sanadi3 have used radioactive labels to determine the lifetime of liver mitochondria. When mitochondria age and their function deteriorates, they invariably swell, critical eoenzymes leak out of the interior, the mechanisms which control the configurational state become inoperative, and finally, the membranes enveloping the mitochondrion perforate and the internal contents are extruded into the cytoplasm of the cell. 4 Probably much the same kind of disruptive molecular catastrophe befalls the mitochondrion as befalls the individual enzyme. The catastrophe is infrequent, but the probability is high that within a certain time period the catastrophe will take place with the inevitable end point of mitochondrial "death." The mitochondrion, like the enzyme, cannot replicate itself. When it dies, it must be replaced by new mitochondria generated de novo by the hereditary apparatus of the cell. The one difference between the mitochondrion and the enzyme is that the mitochondrion has a control mechanism which can regulate, within narrow limits, the response of the mitochondrion to changes in external conditions. This control mechanism, however, is no protection against
POSTGRADUATE MEDICINE • March 1975 • Vol. 57 • No. 3
the inevitable molecular catastrophe to which all mitochondria and all organelles are susceptible with predictable frequency. 5
Downloaded by [Australian Catholic University] at 18:01 26 August 2017
The Aging Process
Aging, whether of the mitochondrion or of an enzyme, is a consequence of destructive molecular collisions leading to chemical modification of proteins and loss of catalytic function. As far as we know, there is no way of preventing or eliminating such molecular catastrophes. They are intrinsic to the physical world of molecules. All complex molecules of the kind dealt with in biologic systems have prescribed lifetimes by virtue of the intense turbulence to which they are continuously subjected. This aspect of aging, which may be called aging at the molecular level, places a ceiling on longevity. The complex molecules of living systems, be they of the energy, heredity, or control systems, are vulnerable molecules and must be continuously replaceable. The replacement systems are not exempt from this disability. These too contain complex molecules which are vulnerable to molecular catastrophe. There is in the end no way around the inevitable aging and deterioration of specialized multicellular organisms. Aging in a cell is at a higher level of organization. The mammalian red blood cell, which lacks the hereditary equipment for replacement of any of the cellular constituents, is a good example for consideration. This allows us to focus on cell aging without becoming enmeshed in the problem of replacement. The lifetime of a mammalian red blood cell is determined by the stability of its membranes and complex molecules and by the frequency with which these molecules undergo catastrophic inactivation. The red blood cell has basically one organelle, namely, the plasma membrane, and the cell lasts as long as the membrane is intact. The mammalian red blood cell lasts an average of 100 days, give or take a few days. 6 When a red blood cell fails, it leaks hemoglobin, undergoes change from its normal biconcave discoid shape to a sphere, and finally perforates into disorganized fragments. Again, the cause of this cell
Vol. 57 • No. 3 • March 1975 • POSTGRADUATE MEDICINE
DAVID E. GREEN
Dr. Green is in the Institute for Enzyme Research, University of Wisconsin, Madison.
death can be attributed to the inevitable molecular catastrophe which befalls the protein molecules in the plasma membrane. When a sufficient number of such catastrophes have taken place, the stability and function of the plasma membrane become attenuated to the point that the membrane can no longer contain hemoglobin and it ruptures, with loss of cell contents. The red blood cell is an expendable cell, and therefore its aging process is by no means typical of other cells such as cardiac or nerve cells, which have a high degree of built-in replacement capability. Every part which is worn out is, in principle, replaceable, be this part in the cell membrane, the mitochondrion, the sarcoplasmic reticulum, or the actomyosin. In such a cell, the inevitable aging which results from molecular catastrophes is balanced by what may be called replacement therapy. The damaged sector is replaced by an undamaged, newly generated sector. How this replacement is done is still not known, but at least we know that it must go on because cells like cardiac cells and nerve cells can survive as long as the lifetime of the organism. In a sense, the nonexpendable cells "outwit" the aging process by the tactic of continuous replacement. This tactic is insufficient when the cell suffers acute trauma as in a myocardial infarct and the rapidly sustained damage is too extensive to be rectified in time. Under such (Continued on page 152)
149
Problems of Aging
........................................................................................... .... ............ ... ... ..... ...... .... .... ... ... ...... .. .... ... .. .... .. ..... ... ... ... ...... .
When the replacement therapy begins to fail, cell death becomes inevitable. With each irreplaceable cell that dies, Downloaded by [Australian Catholic University] at 18:01 26 August 2017
organ function is diminished, and finally, organismic function is threatened. circumstances, neither the protective control mechanisms nor the replacement therapy can intervene before irreversible changes set in and cell death results. The tactic of replacement therapy is also insufficient when the replicating systems that generate the replacement parts undergo aging and can no longer produce with fidelity the parts to be used in replacement. The picture that finally emerges from this consideration of the component elements in the aging process at the molecular level is that aging is a consequence of the stepwise shift in the balance between the inevitable molecular process of deterioration and loss of function and the replacement of damaged proteins and damaged organelles within individual cells. At the point that the replacement therapy begins to fail, cell death becomes inevitable. With each irreplaceable cell that dies, organ function is diminished, and finally, organismic function is threatened. The chain of causality from the molecular event at the level of enzymes to the integrated behavior of the whole animal is then complete. The consequences of the aging process are different, depending on the cell. The aging of a hair follicle is clearly less serious than the aging of a nerve cell. Both may be irreplaceable, but the loss of the former does not affect the performance of the organism, whereas the loss of the latter is potentially catastrophic as the process of cell death builds up. All this leads up to the notion that the aging process, though uni-
152
versa! in all types of cells, assumes overriding importance in cells of the critical organs-the heart, the nervous system, the brain. If we are to make progress in the tactics for slowing up or arresting the aging process in man, we must fully comprehend the cellular technology for replacement of damaged components such as enzymes, organelles, and membranes. It is the preservation of this technology in the cells of critical organs that is the first line of defense against the aging process. Conclusion
Among the remarkable achievements of molecular biology is the discovery of the control mechanisms which regulate the repair of breaks in nucleic acid arising from chance molecular catastrophes. 7 Here is direct evidence of the operation of one of the intrinsic cellular techniques for repairing the ravages of molecular catastrophes. This is only one component of the replacement therapy technology. What is distressing is the state of our ignorance about the biochemical basis of this technology. The problem of aging at long last can be defined with some precision. The blueprint for the design of meaningful research programs for the study of aging in man can now be constructed. Address reprint requests to David E. Green, PhD, lnsti· tute for Enzyme Research, University of Wisconsin, 1710 University Ave, Madison, WI 53706. REFERENCES 1. Green DE, Goldberger RF: Molecular lnsights Into
2. 3. 4. 5. 6. 7.
the Living Process. New York, Academic Press, lnc, 1967 Green DE, Baum H: Energy and the Mitochondrion. New York, AcademiC Press, lnc, 1970 Fletcher MJ, Sanadi DR: Turnover of liver mitochondrial components in adult and senescent rats. ] Gerontal 16:255, 1961 Lehninger AL: The Mitochondrion. Menlo Park, Calif, WA Benjamin, Inc, 1964 Southard J, Nitisewojo P, Green DE: Mercurial toxicity and the perturbation of the mitochondrial control system. Fed Proc 33:2147-2153, 1974 Bishop C, Surgenor DM (Editors) : The Red Blood Cell. New York, Academic Press, Inc, 1964 Lehman IR: DNA ligase: Structure, mechanism, and funaion. Science 186:790·797, 1974
POSTGRADUATE MEDICINE • March 1975 • Vol. 57 • No. 3
