**3. Natural resistance to senescence**

A medical condition termed persistent thymus has been known for long [37]. In the affected population the thymus is rescued from involution. These individuals, however, have severe defects in their hormonal system, affecting the level of sex steroids. It is the lack of androgen-effect that prevents thymus involution on one hand, but hampers the endocrine system on the other hand. Recently another medical condition termed FPLD3 (familial partial lipodystrophy type 3) has also been associated with the lack of thymus involution [38]. FPLD3 also derails the hormonal system by affecting PPARgamma activity. As for all adipose tissue subtypes, PPARgamma plays a crucial role during thymus adipose involution as well [39]. It has been suggested by others previously based on direct fate-mapping experiments that with senescence thymic adipose tissue develops from the thymic stromal or epithelial compartment [22]. In further support, epithelial to adipose trans-differentiation has been reported to occur as indicated by the presence by EpCAM-1/PPARgamma doublepositive cells at a given time point during thymus senescence. Such cells express cell

surface markers as memories of their fading thymic epithelial identity (EpCAM-1), yet already show signs of their novel adipocyte differentiation program in their nuclei (PPARgamma). Further experiments showed that the medullary compartment is rescued from age-related shrinking in case of PPARgamma deficiency. Prolonged survival of thymus stromal niche provides permissive environment for sustained fresh naïve T cell production as indicated by increased mTrec values. Thymocyte subpopulations were equally supported by PPARgamma deficiency and fresh naive T cells outnumbered memory T cells despite age. The sustained support of fresh naive T cells provides functional advantages even at elevated ages. Oral consumption of foreign T-depended antigen initiates immune tolerance to block potential immune response, even along with parallel immunization. Unfortunately, this tolerance is impaired at old age [40–42] Loss of oral tolerance is a potential link to increasing food intolerance prevalence [43–46]. However, tolerance is rescued by PPARgamma deficiency at senior age [38]. In senior individuals protection from seasonal flu strains declines despite annual vaccination [47–49]. The cause: low levels of neutralizing antibody titers due to lacking naïve T-cells required for T-B cooperation. This, however, is also rescued by PPARgamma deficiency [38].
