IN FOCUS
Aging

Johannes-Müller-Institut für Physiologie, Humboldt Universität (Charité), D-10117 Berlin, Germany

	ARTICLE

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AS RECENTLY ANNOUNCED (23), starting this month "In focus" articles will be regularly published in our journal. These overviews intend to outline the different platforms of scientific exchange that have developed in the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology over the last 2 yr.

In this period of time, over 30 articles have been published that deal with different aspects of aging. These studies range from the detection of various polymorphisms (6), molecular biology techniques (17), and cell physiological observations (5) to modeling (9, 15, 16). In most other studies not specifically addressing developmental aspects, the effect of age on regulatory physiology is controlled, or largely eliminated, by investigating a cohort of uniform age. This is common practice, because old age is often accompanied by profound changes of manifold physiological processes, such as sleep (25), circadian rhythms (7, 8, 20, 27), and thermoregulation (3). With regard to thermoregulatory differences in younger and older humans, it is known that thermoregulatory efficiency is impaired at older ages. The two primary responses to a cold challenge, shivering and vasoconstriction, are less effective in the senescent. The reasons for these age-related modifications are unknown; however, Frank et al. (11) made a considerable contribution to enhance understanding of diminished thermoregulatory response at older age. Cold fluid was given intravenously to decrease core temperature in younger and older individuals. Compared with younger subjects, the elderly revealed significantly lower core temperature thresholds for vasoconstriction, heat production, and plasma norepinephrine responses. Intriguingly, however, the maximum intensities of the vasoconstriction and heat production responses were less in the older compared with the younger subjects. Plasma norepinephrine concentrations increased fourfold in the younger but only twofold in the older subjects during cooling. Moreover, the vasomotor response to norepinephrine was decreased in the older subjects. Thus an age-related reduction in sympathoneural and vasomotor responsiveness was found that attenuates cutaneous vasoconstriction during cold stress. These findings, along with a decreased intensity of metabolic heat production and decreased thermal perception during core hypothermia, show that all major cold-defense mechanisms are impaired with aging. They may also add to the understanding why the elderly cannot efficiently develop fever, as shown in rats (10).

Needless to point out, the patients we teach our students to cure mostly belong to the group of elderly citizens. Much of the recent age-related work published in our journal stems from two areas. One of these fields is digestion, metabolism, and excretory function (1, 2, 18, 19, 22). As shown by Karagiannides et al. (14), adipogenesis, adipocyte size, and metabolic responsiveness change between adulthood and senescence. Remarkably, the expression of CCAAT/enhancer binding protein (C/EBP)-, a key regulator of adipogenesis and fat cell function, diminishes substantially with aging in differentiating cultured preadipocytes. Overexpression of C/EBP- in preadipocytes cultured from old rats restores the capacity to differentiate into fat cells, indicating that downstream differentiation-dependent genes maintain responsiveness to regulators of adipogenesis. Although there are clear changes in metabolism of the elderly, many changes in body functions are falsely related to age rather than to age-related feeding and exercise habits. This was shown by Gupta and associates (12) for insulin-mediated storage of muscle glycogen. Using a novel aging model of rats (F₁ hybrid of Brown Norway × Fischer-344 crosses) and caloric restriction to prevent an increased fat mass at age, these authors showed that it is the increase in fat mass, and not age itself, that determines the decrease in insulin action and glycogen synthesis.

The second area in which many age-related studies have recently been published is cardiovascular research (4, 21, 26). Although resting arterial blood pressure, heart rate, and renal sympathetic nerve activity may not be primarily affected in considerably aged rats, Irigoyen et al. (13) did find clear changes in baroreflex control of heart rate and renal sympathetic nerve activity. In this context, it is interesting that the -adrenergic receptors are desensitized in the elderly without changes in -adrenergic receptor density. Schutzer et al. (24) are likely the first to investigate age-dependent changes in G protein receptor kinase (GRK) activity and expression. This kinase phosphorylates the receptor, thus agonists bind poorly. Intriguingly, their study demonstrates an increased expression of GRK-2, GRK-3, and of -arrestin (which mediates downregulation) at age. These observations can explain the attenuated -adrenergic vasodilatory response with advancing age.

	FOOTNOTES

Address for reprint requests and other correspondence: P. B. Persson, Johannes-Müller-Institut für Physiologie, Humboldt Universität (Charité), Tucholskystr. 2, D-10117 Berlin, Germany (E-mail: pontus.persson{at}charite.de).

	REFERENCES

TOP ARTICLE REFERENCES

1.   Blanton, CA, Horwitz BA, Blevins JE, Hamilton JS, Hernandez EJ, and McDonald RB. Reduced feeding response to neuropeptide Y in senescent Fischer 344 rats. Am J Physiol Regulatory Integrative Comp Physiol 280: R1052-R1060, 2001[Abstract/Free Full Text].

2.   Boesch, DM, and Garvin JL. Age-dependent activation of PKC isoforms by angiotensin II in the proximal nephron. Am J Physiol Regulatory Integrative Comp Physiol 281: R861-R867, 2001[Abstract/Free Full Text].

3.   Brooks-Asplund, EM, Cannon JG, and Kenney WL. Influence of hormone replacement therapy and aspirin on temperature regulation in postmenopausal women. Am J Physiol Regulatory Integrative Comp Physiol 279: R839-R848, 2000[Abstract/Free Full Text].

4.   Convertino, VA, and Ludwig DA. Validity of O_{2 max} in predicting blood volume: implications for the effect of fitness on aging. Am J Physiol Regulatory Integrative Comp Physiol 279: R1068-R1075, 2000[Abstract/Free Full Text].

5.   Daun, JM, Ball RW, and Cannon JG. Glucocorticoid sensitivity of interleukin-1 agonist and antagonist secretion: the effects of age and gender. Am J Physiol Regulatory Integrative Comp Physiol 278: R855-R862, 2000[Abstract/Free Full Text].

6.   Di Maso, NA, Caiozzo VJ, and Baldwin KM. Single-fiber myosin heavy chain polymorphism during postnatal development: modulation by hypothyroidism. Am J Physiol Regulatory Integrative Comp Physiol 278: R1099-R1106, 2000[Abstract/Free Full Text].

7.   Duncan, MJ, and Deveraux AW. Age-related changes in circadian responses to dark pulses. Am J Physiol Regulatory Integrative Comp Physiol 279: R586-R590, 2000[Abstract/Free Full Text].

8.   Edmonds, KE, and Stetson MH. Effects of age and photoperiod on reproduction and the spleen in the marsh rice rat (Oryzomys palustris). Am J Physiol Regulatory Integrative Comp Physiol 280: R1249-R1255, 2001[Abstract/Free Full Text].

9.   Even, PC, Rolland V, Roseau S, Bouthegourd JC, and Tome D. Prediction of basal metabolism from organ size in the rat: relationship to strain, feeding, age, and obesity. Am J Physiol Regulatory Integrative Comp Physiol 280: R1887-R1896, 2001[Abstract/Free Full Text].

10.   Florez-Duquet, M, Peloso E, and Satinoff E. Fever and behavioral thermoregulation in young and old rats. Am J Physiol Regulatory Integrative Comp Physiol 280: R1457-R1461, 2001[Abstract/Free Full Text].

11.   Frank, SM, Raja SN, Bulcao C, and Goldstein DS. Age-related thermoregulatory differences during core cooling in humans. Am J Physiol Regulatory Integrative Comp Physiol 279: R349-R354, 2000[Abstract/Free Full Text].

12.   Gupta, G, She L, Ma XH, Yang XM, Hu M, Cases JA, Vuguin P, Rossetti L, and Barzilai N. Aging does not contribute to the decline in insulin action on storage of muscle glycogen in rats. Am J Physiol Regulatory Integrative Comp Physiol 278: R111-R117, 2000[Abstract/Free Full Text].

13.   Irigoyen, MC, Moreira ED, Werner A, Ida F, Pires MD, Cestari IA, and Krieger EM. Aging and baroreflex control of RSNA and heart rate in rats. Am J Physiol Regulatory Integrative Comp Physiol 279: R1865-R1871, 2000[Abstract/Free Full Text].

14.   Karagiannides, I, Tchkonia T, Dobson DE, Steppan CM, Cummins P, Chan G, Salvatori K, Hadzopoulou-Cladaras M, and Kirkland JL. Altered expression of C/EBP family members results in decreased adipogenesis with aging. Am J Physiol Regulatory Integrative Comp Physiol 280: R1772-R1780, 2001[Abstract/Free Full Text].

15.   Keenan, DM, and Veldhuis JD. Explicating hypergonadotropism in postmenopausal women: a statistical model. Am J Physiol Regulatory Integrative Comp Physiol 278: R1247-R1257, 2000[Abstract/Free Full Text].

16.   Keenan, DM, and Veldhuis JD. Hypothesis testing of the aging male gonadal axis via a biomathematical construct. Am J Physiol Regulatory Integrative Comp Physiol 280: R1755-R1771, 2001[Abstract/Free Full Text].

17.   Kostrominova, TY, Macpherson PC, Carlson BM, and Goldman D. Regulation of myogenin protein expression in denervated muscles from young and old rats. Am J Physiol Regulatory Integrative Comp Physiol 279: R179-R188, 2000[Abstract/Free Full Text].

18.   Lluel, P, Palea S, Barras M, Grandadam F, Heudes D, Bruneval P, Corman B, and Martin DJ. Functional and morphological modifications of the urinary bladder in aging female rats. Am J Physiol Regulatory Integrative Comp Physiol 278: R964-R972, 2000[Abstract/Free Full Text].

19.   Mac, LM, Damasco MC, Igarreta P, and Amorena C. In vitro and in vivo evaluation of proximal tubular acidification in aging rats. Am J Physiol Regulatory Integrative Comp Physiol 280: R1627-R1631, 2001[Abstract/Free Full Text].

20.   Mathews, CE, Wickwire K, Flatt WP, and Berdanier CD. Attenuation of circadian rhythms of food intake and respiration in aging diabetes-prone BHE/Cdb rats. Am J Physiol Regulatory Integrative Comp Physiol 279: R230-R238, 2000[Abstract/Free Full Text].

21.   Narayanan, K, Collins JJ, Hamner J, Mukai S, and Lipsitz LA. Predicting cerebral blood flow response to orthostatic stress from resting dynamics: effects of healthy aging. Am J Physiol Regulatory Integrative Comp Physiol 281: R716-R722, 2001[Abstract/Free Full Text].

22.   Pagliassotti, MJ, Gayles EC, Podolin DA, Wei Y, and Morin CL. Developmental stage modifies diet-induced peripheral insulin resistance in rats. Am J Physiol Regulatory Integrative Comp Physiol 278: R66-R73, 2000[Abstract/Free Full Text].

23.   Persson, PB. A trans-Atlantic step. Am J Physiol Regulatory Integrative Comp Physiol 281: R373-R374, 2001[Free Full Text].

24.   Schutzer, WE, Reed JF, Bliziotes M, and Mader SL. Upregulation of G protein-linked receptor kinases with advancing age in rat aorta. Am J Physiol Regulatory Integrative Comp Physiol 280: R897-R903, 2001[Abstract/Free Full Text].

25.   Shiromani, PJ, Lu J, Wagner D, Thakkar J, Greco MA, Basheer R, and Thakkar M. Compensatory sleep response to 12 h wakefulness in young and old rats. Am J Physiol Regulatory Integrative Comp Physiol 278: R125-R133, 2000[Abstract/Free Full Text].

26.   Thompson, MM, Oyama TT, Kelly FJ, Kennefick TM, and Anderson S. Activity and responsiveness of the renin-angiotensin system in the aging rat. Am J Physiol Regulatory Integrative Comp Physiol 279: R1787-R1794, 2000[Abstract/Free Full Text].

27.   Van Reeth, O, Weibel L, Olivares E, Maccari S, Mocaer E, and Turek FW. Melatonin or a melatonin agonist corrects age-related changes in circadian response to environmental stimulus. Am J Physiol Regulatory Integrative Comp Physiol 280: R1582-R1591, 2001[Abstract/Free Full Text].