**4. Induced rejuvenation**

It has been reported early on that the thymus may be regenerated by a variety of interventions (aka thymic rebound) [50]. FoxN1 (a forkhead class transcription factor) is the mastermind of TEC differentiation [51–55]. FoxN1 has also been shown to promote proliferation [56]. Reducing (but not fully diminishing) FoxN1 expression early on triggers premature thymus involution (aka thymus progeria). The opposite, however, over-expression of FoxN1 efficiently postpones thymus involution [57]. Among secreted factors, Wnt4 and keratinocyte growth factor (aka KGF) have also verified as key factors of both thymic senescence and rebound [58–61]. The onset of adolescence presents a frequently proposed physiological cause for thymic degeneration. In accordance, both chemical and surgical castration that result in sex-steroid ablation (SSA) yield thymic rebound [62, 63]. SSA-triggered thymic rebound correlates with both increased thymus size and thymocyte number leading to increased fresh naive T cell production. At the histological level this is suggested by the recovery of the cortico-medullary junction [64]. Accordingly, systemic hormonal changes associated with senescence partly explain changes observed during thymic senescence. In harmony, deletion of the androgen receptor results in an enlarged thymus and resistance to androgen induced thymus atrophy [65]. This is also in line with reports showing that the thymus reaches peak size and productivity early after birth, and not later at puberty [66–68]. Unfortunately, castrationinduced rebound is only a transient phenomenon, and the thymus re-involutes within a couple of weeks. Apparently, although SSA may trigger the expansion of the thymus, yet does not rejuvenate it [69]. In the case of the thymus, in comparison with other organs, little is known about the molecular and cellular mechanisms that control its development and maintenance. FoxN1 certainly is a mastermind linking development and maintenance of the thymic microenvironment throughout life, yet some TEC differentiation also occurs independent from Foxn1 [70].

### **5. Novel trends of rejuvenation**

Transcription factor FoxN1 - the mastermind of thymus organogenesis and identity - is a known as the molecular target of the glycolipoprotein Wnt4 [71, 72].

**41**

**Author details**

**Acknowledgements**

Krisztian Kvell

University of Pecs, Pecs, Hungary

provided the original work is properly cited.

factors, tissue markers and miRNA species.

Department of Pharmaceutical Biotechnology, Faculty of Pharmacy,

\*Address all correspondence to: kvell.krisztian@pte.hu

*Thymic Senescence*

*DOI: http://dx.doi.org/10.5772/intechopen.87063*

For this reason Wnt4 plays a crucial role in thymus development and maintenance [73–77]. With senescence thymic epithelial cells secrete less Wnt4, however, their Frizzled receptors (Fz4 and Fz6) become up-regulated as compensatory mechanism [78]. It is his loss of Wnt4 expression that allows for thymic adipose involution to develop due to PPARgamma-effect [79, 80]. The Wnt/b-catenin pathway and PPARgamma act as inhibitors of each other hence exogenous Wnt4 can reinforce thymic epithelial identity [79–84]. Wnt4 loses activity when purified, because the Wnt molecules travel in extracellular vesicles (EVs, or exosomes in this case) or on their surfaces [85, 86]. It has been reported that miR27b also specifically inhibits PPARgamma activity [87, 88]. The miRNA species are known travel in EVs and in exosomes as well [89, 90]. The thymus is a rich source of exosomes with immunological relevance in e.g. thymocyte selection [91–94]. As a combination of the above, artificially produced (transgenic) exosomes containing Wnt4 and miR27b in excess can block PPARgamma-effect in thymic epithelial cells thus efficiently

counteracting senescence observed as thymic adipose involution [95].

World population is approaching 7.7 billion as of 2019 [96]. Global population increases due to increasing life expectancy, rather than increasing birth rate. However, increasing lifespan is not proportionally attributed with increasing health-span. As a result social expenses rise and novel solutions are urged. Central immune (thymus) senescence research based novel solutions can potentially improve senior immune fitness through decreasing the incidence of infections, malignant and autoimmune disorders. These could also thus alleviate the current burden on healthcare systems and increase quality of life in the elderly. An ultimate goal is to prolong immune fitness and realign it with constantly increasing lifespan. With aging the thymus shows adipose involution. During this process thymic epithelial cells trans-differentiate into beige adipocytes through an intermediate fibroblast stage. Key molecular events are summarized at the level of transcription

The project has been supported by the European Union, cofinanced by the European Social Fund: Comprehensive Development for Implementing Smart Specialization Strategies at the University of Pécs (EFOP-3.6.1.-16-2016-00004).

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

#### *Thymic Senescence DOI: http://dx.doi.org/10.5772/intechopen.87063*

*Thymus*

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.

It has been reported early on that the thymus may be regenerated by a variety of interventions (aka thymic rebound) [50]. FoxN1 (a forkhead class transcription factor) is the mastermind of TEC differentiation [51–55]. FoxN1 has also been shown to promote proliferation [56]. Reducing (but not fully diminishing) FoxN1 expression early on triggers premature thymus involution (aka thymus progeria). The opposite, however, over-expression of FoxN1 efficiently postpones thymus involution [57]. Among secreted factors, Wnt4 and keratinocyte growth factor (aka KGF) have also verified as key factors of both thymic senescence and rebound [58–61]. The onset of adolescence presents a frequently proposed physiological cause for thymic degeneration. In accordance, both chemical and surgical castration that result in sex-steroid ablation (SSA) yield thymic rebound [62, 63]. SSA-triggered thymic rebound correlates with both increased thymus size and thymocyte number leading to increased fresh naive T cell production. At the histological level this is suggested by the recovery of the cortico-medullary junction [64]. Accordingly, systemic hormonal changes associated with senescence partly explain changes observed during thymic senescence. In harmony, deletion of the androgen receptor results in an enlarged thymus and resistance to androgen induced thymus atrophy [65]. This is also in line with reports showing that the thymus reaches peak size and productivity early after birth, and not later at puberty [66–68]. Unfortunately, castrationinduced rebound is only a transient phenomenon, and the thymus re-involutes within a couple of weeks. Apparently, although SSA may trigger the expansion of the thymus, yet does not rejuvenate it [69]. In the case of the thymus, in comparison with other organs, little is known about the molecular and cellular mechanisms that control its development and maintenance. FoxN1 certainly is a mastermind linking development and maintenance of the thymic microenvironment throughout life, yet

This, however, is also rescued by PPARgamma deficiency [38].

some TEC differentiation also occurs independent from Foxn1 [70].

Transcription factor FoxN1 - the mastermind of thymus organogenesis and identity - is a known as the molecular target of the glycolipoprotein Wnt4 [71, 72].

**5. Novel trends of rejuvenation**

**4. Induced rejuvenation**

**40**

For this reason Wnt4 plays a crucial role in thymus development and maintenance [73–77]. With senescence thymic epithelial cells secrete less Wnt4, however, their Frizzled receptors (Fz4 and Fz6) become up-regulated as compensatory mechanism [78]. It is his loss of Wnt4 expression that allows for thymic adipose involution to develop due to PPARgamma-effect [79, 80]. The Wnt/b-catenin pathway and PPARgamma act as inhibitors of each other hence exogenous Wnt4 can reinforce thymic epithelial identity [79–84]. Wnt4 loses activity when purified, because the Wnt molecules travel in extracellular vesicles (EVs, or exosomes in this case) or on their surfaces [85, 86]. It has been reported that miR27b also specifically inhibits PPARgamma activity [87, 88]. The miRNA species are known travel in EVs and in exosomes as well [89, 90]. The thymus is a rich source of exosomes with immunological relevance in e.g. thymocyte selection [91–94]. As a combination of the above, artificially produced (transgenic) exosomes containing Wnt4 and miR27b in excess can block PPARgamma-effect in thymic epithelial cells thus efficiently counteracting senescence observed as thymic adipose involution [95].

World population is approaching 7.7 billion as of 2019 [96]. Global population increases due to increasing life expectancy, rather than increasing birth rate. However, increasing lifespan is not proportionally attributed with increasing health-span. As a result social expenses rise and novel solutions are urged. Central immune (thymus) senescence research based novel solutions can potentially improve senior immune fitness through decreasing the incidence of infections, malignant and autoimmune disorders. These could also thus alleviate the current burden on healthcare systems and increase quality of life in the elderly. An ultimate goal is to prolong immune fitness and realign it with constantly increasing lifespan.

With aging the thymus shows adipose involution. During this process thymic epithelial cells trans-differentiate into beige adipocytes through an intermediate fibroblast stage. Key molecular events are summarized at the level of transcription factors, tissue markers and miRNA species.
