The ability of rats to regenerate almost 3/4 of their liver in a short time has made them valuable for the study of the factors which intervene in cellular multiplication and differentiation. A study which we made in collaboration with E. F. Taskier has shown the importance of biological age of the individual in these processes. Regeneration is rapidly completed in young animals; much more time is required in the old. Liver regeneration has been seen to be related to the appearance of fats in the form of droplets filling up liver cells. Regeneration follows this first phase. The appearance of the fatty droplets provides a means of judging the velocity of regeneration. The importance of age is shown by the fact that fatty droplets appear early in the liver cells of very young animals, filling up the cells, in the first 24 hours. They appear later—in about two days—in young adults; in three days for middle aged rats; after the fourth day in old animals.

The influence exerted by administration of different agents upon regeneration could also be judged through the changes induced in the appearance of the fatty droplets. The administration of insaponifiable fractions in general has induced an earlier appearance of the fatty cells. Injection of 2 cc. of a 10% solution of the insaponifiable fraction of human or even cow placenta was seen to induce an early appearance of the fatty droplets and a filling up of the liver cells. Even in old rats such changes occurred on the second day, contrasting markedly with control rats of the same age in which this would happen on the fourth day or later. Under the influence of these insaponifiable fractions, the old animals behave like youngsters, from the point of view of liver regeneration.

The opposite effect was exerted by the administration of 1 cc. of a 10% solution in oil of the lipoacids of human placenta or of a 10% solution of cod liver oil fatty acids. Appearance of fatty droplets was delayed. In young animals, the droplets were not seen until the third or even the fourth day. With a high dose such as 2 cc. twice a day, of the same preparation in animals of 150 grams, no fatty droplets appeared at all. It is interesting to note that in animals treated with such large doses of lipoacids, regeneration still takes place even without the appearance of the fatty droplets. In these cases the liver cells are comparatively very small and have compact nuclei, instead of the reticular aspect of the nuclei in the controls.

It is also to be noted that a parallelism was seen between the appearance of fatty droplets in liver cells and the richness of adrenals in sudanophil granules. In cases in which the administration of large amounts of lipoacids was followed by nonappearance of fatty droplets in the liver, the adrenals were found to be entirely depleted of fats.

The influence exerted by the lipids upon liver regeneration confirms the antagonistic role of the two groups of lipids in aging processes. The administration of insaponifiable fractions produces a regenerative response characteristic of young animals, while lipoacids produce the response of aged animals. We have applied these findings to other processes in which age is known to be a major factor—such as in the healing of wounds, and especially of fractures, in older people, where administration of insaponifiable fractions has been seen to change an atonic lesion into a rapidly healing one.

The study of liver regeneration has also indicated qualitative differences between various preparations. It is thus interesting to note that, of all the insaponifiable fractions used, the most active were those from placenta and embryos. The insaponifiable fraction of liver also has shown a special capacity to induce rapid regeneration especially of liver tissue. Higher alcohols have shown much less regenerative effect than the insaponifiable fractions.