Despite vigorous research, there is yet no agreement on the biochemical mechanisms responsible for the loss of replicative potential of diploid cultured cells. In contrasts to the program theories of in vitro cell aging, we propose that, as already suggested by Minot in 1907, senescence is the result of cell differentiation. We further maintain that the fundamental cause of cell aging is an instability of the mitochondrial genome because of a lack of balance between mitochondrial repair and the disorganizing effects of oxygen radicals which arise in the respiring mitochondria of terminally differentiated cells. This probably results in intrinsic mitochondrial mutagenesis which may be followed by endonuclease degradation of the altered mitochondrial DNA.

Spermatogonial stem-cell survival after irradiation injury has been studied in rodents by histological counts of surviving cells. Many studies, including previous work from our laboratory, show that the spermatogonial population demonstrates a heterogeneous response to irradiation. The spermatogonia increase in radio-sensitivity as differentiation proceeds through the sequence As - Apr - A1 - A2 - A3 - A4 - In - B. The stem (As) cell is the most resistant and the B cell is the most sensitive. The purpose of this work is to investigate the response of spermatogonial cell to low doses (less than 10 0 rads) of helium particle irradiation.

Thizalidine carboxylic acid (TCA) is a natural liver metabilite whose Mg-salt increased lifespan of flies and mice (Miquel and Economics, 1979, Exp. Geront.14: 279). We studied the physiological and cellular fine structural effects of various concentrations of TCA in the food of male Drosophila. Flies on 0.3% TCA at 27°C had a reduced oxygen consumption rate (about 20% less than controls) at 3 eks of age while their mating capacity and speed of mating were preserved; the flies lived in various experiments 20–30% longer than controls. Apparently TCA improved the metabolic efficiency of the flies (possibly from less “waste” of energy due to improved mitochondrial coupling). However, flies on 0.9% TCA had a reduced mating capacity and lifespan (:toxicity) while at 0.1% TCA was ineffective. A similar dose-response relationship was found in young flies treated with TCA for 1 week and then deprived of food and water, a procedure found to induce accelerated physiological aging. TCA at the 0.3% and 0.6% level reduced the speed of development and the size of the eclosed flies. Electron microscopic investigation of wing muscle showed that 0.3% TCA had a protective effect on cellular fine structure. Though in starved controls (40% survivors after 25 hours of starvation) there was a total absence of glucogen granules, and a striking and densification of mitochondria, TCA to a large extent protected muscle cells from these effects of starvation.

Ever since Pearl proposed the rate of living theory of aging numerous studies have demonstrated its validity in poikilotherms. In mammals, however, satisfactory experimental demonstration is still lacking because an externally imposed increase of basal metabolic rate of these animals (e.g. by placement in the cold) is usually accompanied by general homeostatic disturbance and stress. The present study was based on the finding that rats exposed to slightly increased gravity are able to adapt with little chronic stress but at a higher level of basal metabolic expenditure (increased 'rate of living'). The rate of aging of 17-mth-old rats that had been exposed to 3.14 times normal gravity in an animal centrifuge for 8 mth was larger than of controls as shown by apparently elevated lipofuscin content in heart and kidney, reduced numbers and increased size of mitochondria of heart tissue, and inferior liver mitochondria respiration (reduced 'efficiency': 20% larger ADP: 0 ratio, P less than 0.01; reduced 'speed': 8% lower respiratory control ratio, P less than 0.05). On the other hand, steady-state food intake per day per kg body weight, which is presumably proportional to 'rate of living' or specific basal metabolic expenditure, was about 18% higher than in controls (P less than 0.01) after an initial 2-mth adaptation period. Finally, though half of the centrifuged animals lived only a little shorter than controls (average about 343 vs. 364 days on the centrifuge, difference statistically nonsignificant), the remaining half (longest survivors) lived on the centrifuge an average of 520 days (range 483-572) compared to an average of 574 days (range 502-615) for controls, computed from onset of centrifugation, or 11% shorter (P less than 0.01). Therefore, these results show that a moderate increase of the level of basal metabolism of young adult rats adapted to hypergravity compared to controls in normal gravity is accompanied by a roughly similar increase in the rate of organ aging and reduction of survival, in agreement with Pearl's rate of living theory of aging, previously experimentally demonstrated only in poikilotherms.

ABSTRACT Morphological,changes,were,observed,in the left ven- tricle of,rat heart,tissue,from,animals,flown,on,the Cosmos,1887 biosatellite,for,12.5 days.,These,tissues were,compared,to the synchronous,and,vivarium,con- trol hearts. While,many,normal,myofibrils,were,ob- served, others exhibited ultrastructural alterations, i.e., damaged,and,irregular-shaped,mitochondria,and,gen- eralized,myofibrillar,edema.,Analysis,of,variance (ANOVA) of the,volume,density,data,revealed,a sta- tistically significant,increase,in glycogen,and,a signifi- cant,decrease,in mitochondria,compared,to the syn- chronous,and,vivarium,controls.,Point counting,indi- cated,an,increase,in,lipid,and,myeloid,bodies,and,a decrease in microtubules, but these changes were not statistically significant. In addition, the flight animals exhibited,some,patchy,loss of protofibrils,(actin and myosin,filaments),and,some,abnormal,supercontracted myofibrils,that,were,not,seen,in,the,controls.,This study,was,undertaken,to,gain,insight,into,the,mecha- nistic aspects,of cardiac,changes,in both,animals,and human,beings,as,a consequence,of space,travel (1). Cardiac,hypotrophy,and,fluid shifts have,been,observed after actual,or simulated,weightlessness,and,raise con- cerns,about,the,functioning,of the,heart,and,circula- tory,system,during,and,after,travel,in space,(2-4). -PHILPOTT, D. E.; PopovA, I. A.; Kxro, K.; STEVEN- SON, J.; MIQUEL, J.; SAPS’, W. Morphological and bio-