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While tumour incidence is known to augment with age, paradoxically tumour growth and metastasis were often found to proceed at a slower rate at late ages. This age-related biological behaviour of tumours actually imposes a differential therapeutic approach to the old cancer patient. Several mechanisms of the age-related reduced tumour progression have been demonstrated: decreased tumour cell proliferation, increased apoptotic cell death, decreased angiogenesis and anti-tumoural immune response changes. We postulated that it might be possible to design age-adjusted treatment modalities based on the mechanisms responsible for the reduced tumour progression rate in the aged. Based on these mechanisms, we compared the effect of different treatments (apoptosis-inducing agents, Hydrocortisone and Adriamycin, anti-angiogenic agent, TNP-470, and immunomodulators-Levamisole and BCG) on two experimental tumours (B16 melanoma and AKR lymphoma) growing in young and old mice. Most treatments showed, in both tumours, a higher inhibitory effect on tumours growing in old mice than on those developing in young ones, to our knowledge, a feature not described before for anti-tumoural agents. We suggest that designing ageing conditions in tumours of young patients might possibly alleviate neoplastic aggressiveness in these patients as well.

Numerous data demonstrate a lower aggressiveness of tumors in aged as compared to young patients. The mechanisms underlying this phenomenon have not yet been completely elucidated. Several mechanisms have been shown, such as reduced tumor cell proliferation, increased apoptosis, immune response modifications and reduced angiogenesis in aged organism tumors. In the present study we report an incidentally found, not yet described mechanism, of the age-related reduced tumor progression, namely a decreased ploidy in B16 melanoma growing in old (near diploidy) as compared to young mice (tetraploidy). We surprisingly observed that tumor cells from aged mice were of smaller cell and nuclear size than those of young animals. Flow cytometry forward scatter data also showed a smaller cell size of melanoma cells from old mice. DNA flow cytometry profile comparison demonstrated that while B16 melanoma cells from young animals contained a high percentage of tetraploid cells, those derived from old animals were mostly close to diploid. A high importance has recently been attributed to aneuploidy as being at the origin of the genetic instability of neoplasia. Our results may support this notion. The transit from tetraploidy to near euploidy in melanoma cells growing in aged mice might avoid the genetic instability inherent to tumor progression.

While tumor incidence increases with age, tumor growth and metastasis often proceed at a slower rate in aged organisms. The mechanisms underlying this age-related reduced tumor development may suggest therapeutic modalities appropriate for the aged. Decreased tumor aggressiveness in the old was shown to be related to altered immune response. Consequently, the aim of the present study was to assess whether cancer immunotherapy has an age-dependent effect. Only a few studies have compared cancer immunotherapy efficiency as a function of age, most showing lower inhibition in older animals. In the present study, we tested the effect of two immunomodulators, levamisole and BCG, on two tumors, B16 melanoma and AKR lymphoma, in mice of different ages. We demonstrated a higher efficiency of immunotherapy in aged as compared to young mice, particularly at low immunomodulator doses. While decreased T cell function during aging is apparently established, nonspecific immunity is more preserved or even enhanced in later life. We found an increased number of macrophages in tumors of old compared to young mice and an increase in MAC-1+ cells in old levamisole-treated compared to non-treated mice. The stronger therapeutic effect of this immunomodulator in old mice might thus be due to an increased macrophage-mediated anti-tumoral effect.

Relatively few studies have been published with regard to modification of apoptosis in normal tissues as a function of ageing. The majority of these studies demonstrated an increase in programmed cell death (PCD) with age. However, opposite results, namely loss of apoptotic control with age, have also been reported. In the present study, we examined proliferation and apoptotic cell death in spleens of C57/BL mice of different ages. A tendency towards decrease in cell proliferative capacity was seen with age. By contrast, apoptosis was increased in spleens from aged animals. Moreover, the proliferative cell/apoptotic cell ratio decreased in function of age. Ladder type DNA degradation was much more pronounced in DNA derived from splenocytes of old mice. These results were supported by a decrease of Bcl-2 and an increase in Fas receptor expression as well as by increased activation of caspases 8, 3 and 9 in splenocytes from aged animals. In addition, cell surface molecular markers recognizable by macrophages in apoptotic cells, namely decreased sialic acid concomitant with increased unmasking of galactose residues, were more pronounced on splenocytes from old mice than on those from young animals. In addition to the experimental evidence which supports a role of apoptotic cell death in ageing, a series of theoretical reasoning, which could also favor this possibility, are discussed.