338 Elephants as a comparative species for aging research: From longevity and social complexity to unique biological mechanisms.

Abstract Aging is a general phenomenon that affects all mammals, yet there is considerable variation in the aging phenotype both within and between species. Some individuals maintain robust cognitive function and functional wellbeing well into old age while others experience significant impairments. Despite substantial investment in aging research, we still do not why such variation exists. Thus, it is increasingly important to elucidate the mechanisms of and observed individual variability in aging and aging-associated diseases. One gene that may play a disproportionate role in aging is TP53. TP53 encodes for the protein p53, which is primarily known for its role in cancer and slowing cell growth while damage is repaired or initiating cell death if stress is overwhelming. However, TP53 is involved in several hallmarks of aging. TP53 maintains genomic integrity, regulates cellular senescence, influence mitochondrial health, and modulates various metabolic pathways (e.g., IGF-1 regulation, mTOR inhibition), in addition to playing a role in brain health and cognitive function. Interestingly, elephants have on average 20 copies of TP53, with variation in the number of copies within and between elephant species. Elephants are the only known mammal with more than two copies of TP53 and the only known mammal that has TP53 copy number variation. Elephants have a long lifespan, capable of living into their 7th or 8th decade of life, typically give birth to a single offspring, and demonstrate slow maturation. Elephants’ fitness depends on social bonds, memory, and complex cognition. Elephants live in a complex fission-fusion society, with adult females remaining with their natal families and males leaving at puberty and forming bachelor herds. Breeding herds are led by an older-aged matriarch, serving as the family’s repository of knowledge. Both older aged males and females serve as the hub of social and ecological knowledge within their network. Yet, elephants have been largely overlooked as a comparative species in aging research. We have established elephants for aging and cognitive aging research. By comparing orphaned to non-orphaned wild elephants, we have started to investigate the role of early life trauma on health and pace of aging. Our pilot data have demonstrated that orphan elephants display different hormonal profiles by age compared to non-orphaned elephants. We are currently analyzing how biological age compares to chronological age in orphaned elephants, the differences in pace of aging. We have established the first, and only, national elephant brain database to investigate cognitive changes with age in elephants. Preliminary data demonstrates that elephants may not display neurodegeneration based on neurofilament light concentrations and the staining of brain tissue from one, 52-year old female Asian elephant. We are currently developing cognitive assessments for wild elephants to investigate the relationship between TP53 copy number and cognitive performance.