There is extracellular pigmentation associated with aging in blood vessels. Atheromatous plaques are reported to contain ceriod (21) and lipid peroxides (31). Preparations of acid-solubilized elastin from older animals appear more yellow. This yellow fluorescent pigmentation associated with elastin is also found in ligumentum-nuchae elastin. Partial hydrolyzates of elastin prepared with either elastase or dilute acid are yellow and fluorescent. Fluorescent pigments can be prepared from both partial and complete hydrolyzates (32, 33). Loomeijer (33) believes that lipid-soluble pigments derived from elastase hydrolyzates are derived from auto-oxidized lipid. Work in our own laboratory, as yet unpublished, also causes us to believe that the water soluble pigments of both elastase and acid hydrolyzates are derived from auto-oxidized lipid.

The degree of functional impairment from the accumulation of such pigment is difficult to evaluate. Strehler, Mark, Mildvan, and Gee (19) find that lipofuscin can account for 3 percent or more of the wet weight of cardiac muscle. Nishida and Kummerow (34) report that linoleic peroxide interacts with betalipoprotein in such a way as to alter its electrophoretic pattern, and they suggest that lipid peroxides may play a role in the accumulation of lipid in intima. Interpretation of the relationship between auto-oxidation and aging is complicated by the observation that accumulation of age-associated pigments in neurons is accelerated by deficiency in vitamin E, administration of acetanilid, and stress (29).

CONNECTIVE TISSUE

Interest in the role of connective tissue in aging arose from the fact that unquestionably there are differences between the connective tissue of young and of old animals (35). Both the amount and the character of connective tissue may change. In some tissues, the disappearance of cells is accompanied by replacement of the cells by elements of connective tissue.

Changes in connective tissue can arise from a variety of causes, including alterations in endocrine function (36) that stem from changes in the types of cells represented in the total population, or from chemical changes within the extracellular phase. Gross (37) has suggested that chemical changes similar to the extra cellular changes occur within cells during aging, for which the aggregation of collagen might serve as a model.

In connective tissue there are changes in the mucopolysaccharides present. Davidson, Woodhall, and Baxley (38) report a gradual accumulation of keratosulfate with age in cartillage, nucleus pulposus, and other tissues.

With advancing age collagen becomes tougher, more crystalline, and more difficult to dissolve. Elastin in human blood vessels appears less elastic and fragments with age. This fragmentation is associated with the calcification and pigmentation (39).

In the ground substance there may be an increase in density and aggregation. The significance of such changes is difficult to evaluate, but they may influence the nutrition of cells. Gersh and Catchpole (40) postulate that all interchanges between ground substance and epithelium must occur through two basement membranes, consisting of aggregated round substance, the permeability of which which probably decreases with age. However, if a dispersed colloid aggregates into a more aggregated and a more aqueous phase, diffusion through the aqueous phase may increase. In one of the few attempts that have been made to measure diffusion in young and old tissue, Kirk and Laursen (41) actually found increased diffusion coefficients for nitrogen, oxygene, carbon dioxide, lactate iodide, and glucose in nitima and media of older subjects. In some instances aggregation may decrease in senescence. Banfield and Brindley (42) report that the extractability of abdominal skin collagen in 0.1 percent acetic acid increased in subjects between 40 and 80 years of age.

The question of decreased vascularization and arteriocapillary fibrosis of aging tissue is another aspect of the problem of diffusion of essential nutrient. Changes occur with age in the reserve supply of blood and in the distribution of blood to issue. The diminution in cardiac output, with age, of approximately 1 percent a year (15-17) is in part a reflection of increased peripheral resistance. It is important that all the factors responsible for this increased resistance be recognized, and that morphological changes in the barriers between capillaries and cells be analyzed both in terms of physical chemical changes in mucopolysaccharide, collagen, and elastin and in terms of the properties of the living cells of the vessels. The question of the vascularity of aging tissue is reviewed by Landowne and Stanley (43), and by Handler in the recent AAAS symposium on aging (17).

LIABILITY OF MACROMOLECULES

It is possible that aging results from chemical changes in irreplaceable macromolecules (44). Altered molecules may accumulate in postmitotic cells and in elements of connective tissue with limited rates of replacement.

The time dependent chemical changes postulated may be of a variety of types, and may include thermal denaturation involving unfolding of tertiary structures (45), hydrolysis of amide and peptide bonds (46), and oxidation (47). Among the proteins which might not survive a lifetime of incubation at 38° C. is the extracellular protein elastin. Since it is less crystalline than collagen, it does not have the added protection of extensive hydrogen bonding to protect it against thermal denaturation and other deleterious chemical changes.

AGING AND THE GENE

There is evidence to support the belief that many of the changes which accompany aging occur in the nucleus. Such evidence includes the observation of abnormal nuclei and abnormal cell division in senescent animals (8), as well as the difficulty which adult tissue has in initiating the first mitotic events in tissue culture or after stimulation.

Adherents of the theory that aging is centered in the nucleus generally believe either that aging is an extension of normal differentiation or that it is due to accidental genetic noise.

The first group points out that, while we as individuals may view aging as a catastrophe, it probably serves a useful evolutionary purpose in insuring succession of generations. Insect physiologists and plant physiologists are particularly likely to hold this view. Many insects, in the adult form, have a relatively short life expectancy and may even be born without mouth parts. In such insects differentiation produces a phenotype with a limited life expectancy. The death of an annual plant often appears to be the final step in an orderly development. One may therefore argue that aging is a deliberate event, consisting of differentiation to a point where the interdependence of tissue and cells is incompatible with the indefinite life of the total organism. The deaths of individuals, could however, contribute to the survival of the species by insuring a progression of generations and reducing competition for the food supply between young and old. Dobzhansky has ably presented aging as an adaption of evolution (48).

A second group holds the view that aging arises from genetic noise or random somatic mutations. Henshaw (49), Failla (50), Szilard (51), and Strehler (16) have all discussed theories of aging based on somatic mutation. These are reviewed by Glass (52) in the recent AAAS publication on aging. The rate constant for somatic mutations viewed as chemical reactions would be very small, possibly of the order of 10-13. If genetic material had the thermal stability of purified DNA (53), there would be little probability of thermal mutation, because of the great stability of the hydrogen-bonded DNA helix. On the other hand, in certain cells, genes may be considerably less stable than purified DNA. The rate constant for thermal mutation of Escherichia coli and Bacillus subtilis is of the order of 1×10-° at temperatures between 55° and 60° C. (54). Human genes of this order of stability might undergo considerable spontaneous somatic change at 38° C. Such deductions, however, must remain speculative until they can be made to rest on firmer experimental evidence. It will be difficult to demonstrate that random somatic mutations do occur in aging tissue, particularly if such mutations are truly random. However, an effort should be made to ascertain whether clones of cells from aging individuals have altered biochemical properties. The graying of hair might be an example of a somatic mutation in aging melanocytes (14).

A particular aspect of genetic interest concerns the instructive theory of antibody formation. Is there an impairment in self-recognition in aging animals due to alteration in either antigen or antibody.

Somatic theories of aging have appeal to those who feel that ionizing radiation also produces somatic mutations, for such theories would explain the similarity between aging and radiation injury.

FREE RADICALS

The similarity between certain aspects of radiation injury and aging may reflect common physiological and cellular impairments or, as suggested by Harman (55), may be due to analogous chemical events, such as free radical reactions (56), occurring in both radiation-induced and normal aging. Concepts

based on the chemistry of the free radicals produced by ionizing radiation have proved very helpful in explaining the biological effects of such radiation (57). There is a growing body of evidence, based on findings of an accumulation of pigment believed to arise from auto-oxidized lipid, that auto-oxidation occurs insenescent tissues. It is thought that auto-oxidation proceeds by a free radical mechanism with formation of peroxides and of both carbon and oxygen radicals. More attention should be given to the substances which might initiate such reactions in tissue, such as trace metals, hematin, hydrogen peroxide, or oxygen itself. Free radical hypotheses have the attractive feature of suggesting that preventive therapy with specific antioxidants is a possibility.

SUMMARY

It should be apparent that while no one really understands all the fundamental mechanisms underlying the aging process, progress is being made, and theories are being advanced which may be tested in the laboratory.

REFERENCES

1. B. Gompertz, Phil. Trans. Roy. Soc. London A115, 513 (1825).

2. A. Comfort, The Biology of Senescence (Rinehart, New York, 1956); R. Pearl and J. R. Miner, Quart. Rev. Biol. 10, 60 (1935).

3. H. B. Jones, Advances in Biol. and Med. Phys. 4, 281 (1956).

4. B. L. Strehler and A. S. Mildvan, Science 132, 14 (1960).

5. N. W. Shock, Geriatrics 12, 40 (1957).

6. J. E. Birren, H. A. Imus, W. F. Windle, Eds., The Process of Aging in the Nervous System (Thomas, Springfield, Ill., 1959) ; J. E. Birren, Ed., Handbook of Aging and the Individual (Univ. of Chicago Press, Chicago, Ill., 1959).

7. N. W. Shock, in "Aging-Some Social and Biological Aspects," Publ. Am. Assoc. Advance Sci. No. 65 (1960).

8. W. Andrew, in The Older Patient, W. Johnson, Ed. (Hoeber, New York, 1960).

9. E. T. Engle and G. Pincus, Ed., Hormones and the Aging Process (Academic Press, New York, 1956); G. Pincus, in "Aging-Some Social and Biological Aspects," Publ. Am. Assoc. Advance. Sci. No. 65 (1960).

10. C. H. Barrows, Jr., M. J. Yiengst, N. W. Shock, J. Gerontol. 13, 351 (1958). 11. C. H. Barrows, Jr., J. A. Falzone, Jr., N. W. Shock, ibid. 15, 130 (1960). 12. E. C. Weinbach and J. Garbus, Gerontologia 3, 253 (1959).

13. C. H. Barrows, Intern. Congr. Gerontol., 5th Congr., San Francisco (1960), abstr.

14. C. T. Fitzpatrick, P. Brunet, A. Kukita, in The Biology of Hair Growth, W. Montague and R. A. Ellis, Eds. (Academic Press, New York, 1958). 15. A. C. Upton, J. Gerontol. 12, 306 (1957).

16. B. L. Strehler, Quart. Rev. Biol. 34, 117 (1959).

17. P. Handler, in "Aging-Some Social and Biological Aspects," Publ. Am. Assoc. Advance. Sci. No. 65 (1960).

18. O. Heidenreich and G. Seibert, Arch. pathol. Anat. u. Physiol. Virchow's 327, 112 (1955).

19. B. L. Strehler, D. D. Mark, A. S. Mildvan, M. Y. Gee, J. Gerontol. 14, 430 (1959).

20. H. Heyden and B. Lindstrom, Discussions Faraday Soc. No. 9 (1949) (1950), p. 436.

21. H. E. Schornagel, J. Pathol. Bacteriol. 72, 267 (1956).

22. F. S. Labella, Federation Proc. 19, 143 (1960).

23. A. G. E. Pearse, Histochemistry, Theoretical and Applied (Little, Brown, Boston, 1960).

24. B. Harman, J. Gerontol. 12, 199 (1957).

25. S. Bergstrom and R. T. Holman, Advances in Enzymol. 8, 425 (1945). 26. A. M. Gaddis, R. Ellis, G. T. Currier, Food Research 24, 283 (1959).

27. A. L. Tappel, Arch. Biochem. Biophys. 54, 266 (1955); W. G. B. Casselman, J. Exptl. Med. 94, 549 (1951).

28. A. S. Mildvan and B. L. Strehler, Federation Proc. 19, 231 (1960); paper presented at the 5th International Congress of Gerontology, San Francisco (1960).

29. N. M. Sulkin and P. Srivanij, J. Gerontol. 15, 2 (1960).

30. D. Duncan, D. Noll, R. Morales, ibid 15, 366 (1960).

31. J. Glavind, S. Hartman, J. Clemmesen, K. E. Jensen, H. Dam, Acta Pathol. Microbiol. Scand. 30, 1 (1952).

32. A. Karkela and E. Kulonen, Acta Chem. Scand. 8, 1434 (1957); 13, 814 (1959).

33. F. J. Loomeijer, Nature 182, 182 (1958); Neth. Soc. Physiol. Pharmacol. 8, 518 (1959).

34. T. Nishida and F. A. Kummerow, J. Lipid Research 1, 450 (1960).

35. A. Von Meyer and F. Verzar, Gerontologia 3, 184 (1959).

36. H. Sobel, G. Gabay, E. T. Wright, I. Licktenstein, N. H. Nelson, J. Gerontol. 13, 128 (1958).

37. J. Gross, in Cellular Basis of Aging, G. H. Bourne, Ed. (Pitman, London, in press).

38. P. A. Davidson, B. Woodhall, W. Baxley, Intern. Congr. Gerontol., 5th Congr., San Francisco (1960), abstr.

39. E. I. Kanabrocke, I. G. Fels, E. Kaplan, J. Gerontol. 15, 383 (1960); A. I. Lansing, Ed., The Arterial Wall (Williams and Wilkins, Baltimore, 1959).

40. I. Gersh and H. R. Catchpole, Perspectives in Biol. Med. 3, 282 (1960). 41. J. E. Kirk and T. J. S. Laursen, J. Gerontol. 10, 245 (1955).

42. W. G. Banfield and D. C. Brindley, Surg. Gynecol. Obstet. 109, 367 (1959). 43. M. Landowne and J. Stanley, in "Aging-Some Social and Biological Aspects," Publ. Am. Assoc. Advance. Sci. No. 65 (1960).

44. F. M. Sinex, J. Gerontol. 12, 190 (1957).

45. F. H. Johnson, H. Eyring, M. J. Polissar, The Kinetic Basis of Molecular Biology (Wiley, New York, 1954), p. 271.

46. F. M. Sinex, J. Gerontol. 15, 15 (1960).

48. T. Dobzhansky, Ann. N.Y. Acad. Sci. 71, 1243 (1958).

49. P. Henshaw, G. Stapleton, E. R. Riley, Radiology 49, 349 (1947).

50. G. Failla, Ann. N.Y. Acad. Sci. 71, 1124 (1958).

51. L. Szilard, Proc. Natl. Acad. Sci. U.S. 45, 193 (1959).

52. B. Glass, in "Aging-Some Social and Biological Aspects," Publ. Am. Assoc. Advance. Sci. No. 65 (1960).

53. P. Doty, J. Marmur, J. Kigner, C. Shildkraut, Proc. Natl. Acad. Science U.S. 46, 461 (1960).

54. S. Zamenhof and S. Greer, Nature 182, 611 (1958).

55. D. Harman, J. Gerontol. 11, 298 (1956).

56. G. A. Russell, J. Chem. Educ. 36, 111 (1959).

57. Z. M. Bacq and P. Alexander, Fundamentals of Radiology (Academic Press, New York, 1955).

METROPOLITAN HOSPITAL,
METROPOLITAN HOSPITAL CLINICS,

1800 Tuxedo Avenue, Detroit, Mich., December 5, 1961.

Senator BENJAMIN A. SMITH,

Committee on Labor and Public Welfare,

Senate Office Building, Washington, D.C.

DEAR SENATOR SMITH: I regret very much my inability to respond to your invitation of November 17 to be present at the hearings of the Special Committee on Aging in Springfield and Boston November 29 and December 1.

As a supporter of Senator Hill's S. 1071 and also H.R. 4222, I would have appreciated the opportunity to listen and possibly participate in the discussion. The enclosed broadcast which I was asked to give over station WBAI in New York and San Francisco may be of interest to you or Senator Hill. Sincerely,

ALLAN M. BUTLER, M.D.,
Director of Clinical Services.

BROADCASTS GIVEN OVER RADIO STATIONS IN NEW YORK AND SAN FRANCISCO BY DR. ALLAN M. BUTLER

Because of the confusion resulting from prejudice, misleading and, at times, false statements about financing medical care of the aged under the provisions of the Kerr-Mills AMA-endorsed act, i.e., Public Law 86-778, and of the KingAnderson bill (the administration bill) now before Congress, an attempt to outline briefly what both are and are not seems desirable.

The Kerr-Mills Act, Federal law 86–778, makes Federal support available for State welfare medical care. The means test of eligibility for welfare medicine

varies from State to State; for example, the maximum income per year per person varies according to State from $500 to $1,800, or per couple from $1.500 to $3,000 with maximum capital resources varying from $750 to $7,500, including assets of adult children, who, in some States, must contribute toward support of the needy before any medical assistance can be made available. Where the lower figures pertain many medically needy will not be eligible. Should the liberal eligibility of some States and the unlimited services of the Federal law be adopted generally, 75 percent or more of the 16 million aged might be eligible for unlimited medical care under the State laws that implement the Kerr-Mills Act. Clearly, the costs could add up to a very large sum, of which 20 to 80 percent would be provided by the Federal Government from general tax funds. Yet this law has not been denounced as socialized medicine or even as a foot-in-the-door of socialization, though it surely is and seems a poor form of such.

Question. Dr. Butler, why is Public Law 86-778 (the Kerr-Mills Act) a poor form of socialized medicine?

Dr. BUTLER. Because this bill provides "free medicine," since the majority of those eligible will be paying little into the general tax funds from which the Federal and State Governments will cover costs. Moreover, this law does not encourage individual self-reliance or foresight in making provision for meeting the cost of medical care in old age when you need most care and can least afford it. It does not prevent pauperization by illness. It introduces inherent opportunity for political influence and corruption in the determination of eligibility by politicians or the local bureaucrats that administer the costly means test. It tends to support and extend the poor fragmented quality of current welfare medicine. It limits the choice of doctor by patient to those doctors who elect to serve welfare patients and much of the medical care is given without free choice at welfare or charity hospitals.

Thus the Kerr-Mills Act is almost everything the American Medical Association objects to.

So it is strange indeed that this is the law the AMA endorses, saying it "preserves the quality of medical care maintaining the patient's freedom of choice."

Question. How about the King-Anderson bill, Dr. Butler?

Dr. BUTLER. The King-Anderson bill (the administration bill) now before Congress is a very different bill serving a different purpose. This bill proposes an extension of the benefits to aged beneficiaries under the old-age, survivors and disability insurance programs of the Social Security and Railroad Retirement Acts, by including defined hospital, nursing home, and home health services.

It thus provides through existing social security the means of prepaying during working years for the medical care of old age. This care will then be received as a respected paid-up right. It will avoid for many the indignity of charity and the poor fragmented quality of current welfare medicine. If the American people through the democratic process freely choose to make this bill law they will freely choose to enable people to practice self-reliance and foresight by prepaying during working years for the medical care required in old age. In so doing, they, as self-reliant people, will lessen the charity burden to society imposed in becoming a welfare recipient of free medicine. There will be no inherent political influence by the bureaucracy that administers a costly means test. There should be no ill-defined cost to be met from general tax funds. There will be the same free choice of physician by the patient that he has had during his working years—indeed, if he has had a personal or family physician he can continue that relationship with the physician of his choice. The bill states that the benefits specified would be provided "in a manner consistent with dignity and self-respect of each individual, without interfering in any way with the [patient's] free choice of physicians or other health personnel or facilities without exercise of any Federal supervision or control over the practice of medicine by any doctor." And later, the bill states, "Nothing in this title shall be construed to authorize any Federal officer or employee to exercise any supervision or control over the practice of medicine.” Yet the AMA says the bill "includes loss of freedom. Your freedom to choose your own doctor. We must all recognize that when the physician is socialized, his patient is socialized." And continuing the AMA says, "It would lower the quality of health care, with remote and impersonal bureaucratic control replacing the confidence and closeness of the doctor-patient relationship."

The fact is that the bill does not socialize the physician, as it does not affect physician services nor does it affect free choice of doctor-patient relationship,