How African Animals Learn From Their Elders

Introduction

Aging is a complex and multifaceted process with species-specific characteristics. Differences amid species can be informative, and accept the potential to reveal the causes and consequences of aging across variation in life history, ecology, and phylogeny (Austad, 1997). Instructive species for comparative investigation include those that share relevant characteristics with humans (Austad, 2009). Elephants are particularly fascinating in this regard.

Like humans, elephants are K-selected animals: they generally give birth to single offspring, have slow maturation, and long lifespans. Elephants are the second longest living terrestrial mammal, behind only humans (Moss, 2001; Sukumar, 2003; Wittemyer et al., 2013; Turkalo et al., 2018). In fact, in a nearly 50 years study of wild elephants in East Africa, the life expectancy of female elephants at nativity (mean, 46.7 years) was reported to exceed that of Hadza hunter-gatherers living nearby (35.6 years) (Moss et al., 2011; Blurton Jones, 2016). Elephants are i of the slowest reproducing terrestrial mammals, with the longest gestational period (Moss, 1983) and have an age of sexual maturity and an interbirth interval comparable to those of humans (Moss, 2001; Wittemyer et al., 2013) (Table 1). They have i of the largest proportional postmaturation to prematuration ratios, possibly surpassing that of humans. Information technology is not only elephants' general traits relative to aging, only their cognitive abilities, emotional complexity, and potent social ties that make them particularly appealing for comparative investigation.

Tabular array 1. Comparative life history of the Amboseli, Kenya, African savanna elephants and Hadza hunter-gatherers.

Although humans and elephants share many characteristics of interest, they are not evolutionarily closely related. The separate lineages leading to elephants and humans diverged approximately 100 1000000 years ago (mya). Thus, studying elephant aging in a comparative perspective may reveal fundamental physiologic mechanisms associated with crumbling. For case, it may prove beneficial to investigate whether elephants develop age-related diseases to the same extent equally humans, when living to comparable ages. This is of particular relevance every bit historic period-associated diseases are a growing public health outcome, and one major limitation of ongoing therapeutic research is the lack of animal models that accurately translate to people. To accost this business organisation, newer, and mayhap more appropriate models, similar elephants, are needed. Thus, emphasizing the importance of the comparative perspective, the aim of this article is to highlight the unique backdrop of elephants and why studying them tin push aging research forrad.

Evolution and Longevity

The family Elephantidae was once a flourishing group of the order Proboscidea, living throughout much of Africa, Eurasia, and the Americas (Shoshani, 1998). Only iii species even so survive: the African savanna (Loxodonta africana), African forest (Loxodonta cyclotis), and Asian (Elephas maximus) elephants (Gobush et al., 2021). Elephants evolved from an ancestry within the afrotherian clade (which also includes manatees, hyraxes, aardvarks, tenrecs, elephant shrews, and golden moles) (Glickman et al., 2005). Mitochondrial DNA analyses suggest that elephants (as well every bit manatees and hyraxes) take a common aquatic ancestor (de Jong, 1998; Mirceta et al., 2013). African elephants diverged from the lineage leading to Asian elephants (and mammoths) approximately 7.six mya, while African savanna and forest elephants diverged approximately four.0 mya (Rohland et al., 2007).

Ane of the defining characteristics of all extant elephants is their longevity. Wild savanna and forest elephants, and zoo and semi-captive Asian elephants are known to live into their 7th decade of life (Lee et al., 2012; Keele, 2014; Lahdenperä et al., 2014; Chapman et al., 2019), with some Asian elephants documented to live into almost their 80s (Lahdenperä et al., 2014). Wild elephants take been living to advanced ages for millennia, without the aid of science or medicine. Such longevity is rare in any terrestrial mammal, which suggests that elephants have evolved mechanisms to protect confronting aging diseases.

In fact, information technology is possible that changes in cistron expression due to DNA methylation can exist used as a mark of longevity with potential mechanistic influence. This line of thinking has led to the recent development of various epigenetic clocks to measure biological historic period. One of the well-nigh unremarkably applied epigenetic clocks (the Horvath clock) was recently used to examine the rate of accumulation of DNA methylation marks in savanna and Asian elephants, and to create a dual human-elephant clock (Prado et al., 2021). Interestingly, most CpGs demonstrate opposite crumbling effects between humans and elephants, including genes associated with respiratory arrangement processes, cyclic rhythms, mitochondrial office, and some cancer-related signatures (Prado et al., 2021). Researchers have likewise conducted lifespan estimates of extinct Elephantidae species. For instance, by using a lifespan clock, the lifespan of the woolly mammoth (Mammuthus primigenius) and that of the directly-tusked elephant (Palaeoloxodon antiquus) were estimated to be lx years (Mayne et al., 2019), like to what is observed in the extant elephant species.

Considering their long lifespan, the age at which female and male person elephants start reproducing is relatively belatedly. Savanna and Asian female person elephants may showtime to conceive at 11–14 years of age and give nativity every three–4 years (Moss et al., 2011). Forest elephants announced to start reproducing subsequently in life, at 20 years of age on average, with interbirth intervals of every v–6 years (Turkalo et al., 2017). Because footling is known about forest elephants, it is unclear whether their comparatively delayed primiparous historic period is representative of forest elephants in general or is specific to this item population studied. Nevertheless, while some female Asian elephants may experience an extended post-reproductive phase (Chapman et al., 2019), females from all three species are capable of reproducing into their 60s (Moss, 2001; Lahdenperä et al., 2014; Turkalo et al., 2018).

Males have a unique combination of behavioral and physiologic traits that reflect the intense pressure to compete for access to estrous females [in general, females are in estrous for only iii–6 days every 3–9 years, encounter (Blurton Jones, 2016; Mayne et al., 2019) for review]. Males grow throughout much, or perhaps all, of their lifespan, in terms of stature, every bit well as body and tusk weight (Roth, 1984; Haynes, 1993; Lindeque and Jaarsveld, 1993; Lee and Moss, 1995). Males experience musth, unique to elephants, which is characterized by bouts of elevated testosterone and aggression, and heightened sexual activeness. Females adopt larger males and those in musth, which may explain why paternity success steadily increases in males from the mid-20s until it peaks effectually early 50s, after which, it is comparable to a male in his early 40s (Hollister-Smith et al., 2007). This observation suggests male elephants may undergo sexual selection for longevity.

One mechanism allowing elephants to reach longer lifespans may be their multiple copies of the tumor suppressor factor TP53 (Abegglen et al., 2015; Sulak et al., 2016), colloquially known as the "guardian of the genome." Humans have ane copy of TP53, whereas savanna, forest, and Asian elephants are estimated to have 19–23, 21–24, and 19–22 TP53 copies, respectively (Tollis et al., 2020). This is compared to estimates of nineteen–28, and 22–25 TP53 copies in the extinct woolly mammoth and direct-tusked elephant, respectively (Tollis et al., 2020). Other afrotherian species, such as the manatee and rock hyrax, have ii copies of TP53, while Bowhead and Minke whales each accept one, respectively (Sulak et al., 2016). Of the multiple elephant TP53 genes, only ane appears to have a comparable gene construction to other mammals, while the other copies appear to be retrogenes, as they lack true introns (Abegglen et al., 2015). Retrogenes can have functional biological roles (Pink et al., 2011). Indeed, genetic variation at some elephant TP53 retrogenes is conserved beyond all iii extant elephant species, providing evidence of the functionality of at least some TP53 retrogenes (Vazquez et al., 2018; Tollis et al., 2020), and functional TP53 duplicates appear to occur only in the elephant lineage (and perhaps some bats) (Sulak et al., 2016). p53 (encoded by the TP53 gene) is a transcription regulator [reviewed in (Laptenko and Prives, 2006)]. When DNA is damaged, p53 can crusade jail cell-cycle abort, senescence, or apoptosis and/or it can stimulate DNA repair, thereby promoting removal or repair of damaged cells [reviewed in (Williams and Schumacher, 2016)] and suppressing tumors.

Every bit reported recently, TP53 is activated in response to cellular stresses in add-on to Deoxyribonucleic acid impairment (Haupt and Haupt, 2017). Thus, these multiple copies may take various furnishings in response to cell stress (Kastenhuber and Lowe, 2017). Elephants appear to have an enhanced apoptotic response to Dna impairment owing to their extensive number of TP53 (EP53) retrogenes (Abegglen et al., 2015; Sulak et al., 2016) and, every bit a consequence, develop cancer at lower rates than expected for their body size and lifespan (Abegglen et al., 2015; Tollis et al., 2020). Interestingly, Asian elephants announced to develop beneficial tumors and malignant cancer at higher rates than do savanna elephants (Tollis et al., 2020). Considering cancer is an age-related disease, the prevalence is significant in the context of the evolution of extended longevity (Lemaître et al., 2020). Thus, long life requires a filibuster or decrease in cancer occurrence, in addition to a reduction of other aging pathologies (Lucas and Keller, 2020). In addition to its involvement in cancer, p53 has other relevant associations, including its association with Alzheimer'due south disease (Advertizement), and its central role in aging. Thus, elephants provide a unique opportunity to further investigate the potential protective effects of p53 in non only cancer, but aging in general.

Complex Social Bonds, Memory, and Cognitive Ability

Elephants societies are a fluid, fission-fusion system, such that group members alter daily or seasonally (Moss and Poole, 1983; Wittemyer et al., 2005). At the centre of elephant lodge is the family, comprised of female person matrilineal relatives and dependent offspring. The tight-knit family members demonstrate remarkable cooperation, moving, foraging, and making decisions together. Families at times bring together together to grade bond groups, and occasionally course an additional social tier termed clans (Wittemyer et al., 2005). Families are led by a matriarch, who is the primary repository for social and ecological knowledge. Matriarchs are largely responsible for the survival of their whole family. Families with older-aged matriarchs are overall more than successful, in terms of both survival and reproduction. Calves are dependent on their mothers and other family unit members for social support, survival, and learning, constantly being touched, guided, and reassured throughout the get-go years of life. While females remain with their natal herd, normally for life, males depart at an average historic period of 14 years (Moss et al., 2011), after which they will join small, all-male groups, albeit with looser arrangements than the females (Spud et al., 2020). Like to other social species, such as humans and free-living populations of baboons (Holt-Lunstad et al., 2010; Silk et al., 2010), sociality and longevity appear to be positively related in elephants. In improver to beingness disquisitional for family survival, the oldest females (the matriarchs) provide protection for calves, with higher dogie survival in families with grandmothers, and they maintain the social cohesion within the herd (Moss et al., 2011). Behavioral aging, characterized by cognitive decline and social isolation, does not announced to be mutual in elephants (Lee et al., 2016).

Elephants take evolved to rely heavily on their cerebral abilities. Data support that living in socially intricate networks correlates with, and probable encourages, greater cognitive skills (Bates and Byrne, 2007). Unquestionably, elephants excel in long-term, spatiotemporal, and social memory. Evidence from both Asian and African elephant ethological research suggests that elephants likely have strong spatial and episodic memories. They appear to navigate circuitous physical and social environments over hundreds of miles using direct and indirect experience (Jacobson and Plotnik, 2020). Other research has shown that elephants retain long-term memory of reward stimuli (Markowitz et al., 1975), can identify and locate more than 100 out-of-view family members (Bates et al., 2008), and tin can spatially locate waterholes over 100 km distances and extended periods of time (more 3 years) (Polansky et al., 2015). Elephants appear to have learned to discern betwixt human indigenous groups that vary in their level of threat toward elephants (Bates et al., 2007; McComb et al., 2014). Elephants also seem to be unique among non-man animals in that they may showroom behaviors related to "theory of mind", demonstrating cocky-awareness (Plotnik et al., 2010), cooperation with one some other (Plotnik et al., 2011), mourning-like behavior (Goldenberg and Wittemyer, 2020), empathy (Byrne et al., 2008), and consolation (Plotnik and de Waal, 2014).

Elephants' remarkable long-term retentiveness and potent social ties appear to leave them susceptible to psychological trauma. Wild elephant populations have experienced loftier levels of violence (i.eastward., poaching—elephants killed for their tusks). At the acme of poaching in Africa in 2011, approximately 40,000 elephants were illegally killed in just that yr solitary, equating to a possible species reduction of iii% (Wittemyer et al., 2014). Although elephants have processes, rituals, and social structures to respond to trauma, including behaviors that resemble grieving, mourning, and socializing, the magnitude and nature of homo violence has disrupted elephants' ability to use these practices, leading to what has been described equally mail service-traumatic stress disorder (PTSD) (Bradshaw et al., 2005). In i instance, in S Africa, teenaged orphaned male elephants were uncharacteristically trigger-happy, killing over 100 rhinoceroses (an abnormal beliefs for elephants) (Bradshaw et al., 2005). In addition, male elephants with PTSD were responsible for xc% of all male elephant deaths in their community, compared with 6% in relatively unstressed communities (Bradshaw et al., 2005). Calves who survive witnessing their mother (and sometimes their entire families) being killed visually demonstrate an emotion akin to despair. It is possible, and something we are currently investigating, that these traumatized orphaned elephants develop health issues later in life and have accelerated aging, similar to children and wild baboons with higher adverse early life experiences (Felitti et al., 1998; Chocolate-brown et al., 2009; Brown et al., 2010; Tung et al., 2016). Elephants' dependence on social bonds, memory, and knowledge highlights their potential in studying age-related cognitive reject, which may uncover specific adaptations in the wider context of the evolution of cognition.

Encephalon Size and Composition

Brain size has been shown to exist related to torso size, sociality, and lifespan in certain groups of mammals (Street et al., 2017). Species with larger brains (in absolute size and also relative to body size), on boilerplate, demonstrate a greater ability to process and use circuitous information (Holloway et al., 1979; Deaner et al., 2007). Over the course of development, the encephalization caliber (EQ, which is a measure of how much larger a species' brain is than expected past general allometric scaling for a given body size) of Proboscidea has increased by 10-fold, to about ii.0 for extant elephants. Thus, the elephant encephalon is twice as big equally would be expected for an average mammal of the same body size (Shoshani et al., 2006). The adult elephant brain averages around 5 kg (Shoshani et al., 2006; Herculano-Houzel et al., 2014), which is the largest among living and extinct terrestrial mammals, and three times the absolute size of the human encephalon. For big-brained, long-lived species, there is a need to develop improved aerobic free energy production to fuel neuronal activity. When comparing protein evolution associated with encephalon, lifespan, and metabolism betwixt humans and elephants, a convergent pattern is observed (Goodman et al., 2009). Specifically, in comparison to their phylogenetic relatives, elephants and humans have independently evolved and share increased nonsynonymous amino acid substitution rates amid nuclear genes that code for mitochondrial proteins that function in aerobic energy metabolism (Goodman et al., 2009). This adaptive evolution of protein structure in elephants and humans likely minimizes reactive oxidative species, helping to reduce Dna impairment and preserve long-lived neurons (Goodman et al., 2009).

Because elephants have extensive retention abilities, appearing to exceed those of great apes and possibly even humans, information technology is of import to examine specific anatomical encephalon structures. For example, the elephant brain's cerebral gyral design is more complex with more than gyri than in primates, including humans, and carnivores, merely is less complex than in cetaceans (Shoshani et al., 2006), which is a anticipated design given the cortical surface area and thickness (Mota and Herculano-Houzel, 2015). Elephants take the greatest volume of cerebral cortex, with large, nonprimary areas idea to be involved in higher-order brain functions (Hart and Hart, 2010). The hippocampus, which is crucial for the germination and retention of cognitive maps that code for unfamiliar spatiotemporal relationships (Sweatt, 2004), is comparable in absolute size between elephants and humans, albeit proportionally smaller in elephants (Herculano-Houzel et al., 2014) and has the expected architecture for a mammalian hippocampus (Patzke et al., 2014). The elephant temporal lobe is disproportionately large compared with that of humans and expands laterally (Shoshani et al., 2006). Lastly, the elephant's cerebellum has deviated markedly in development. Information technology is the relatively largest compared to the rest of the brain size of all other mammals, and the lateral cerebellar hemispheres are expanded compared to the vermis (Maseko et al., 2012), although there are mammals that accept greater lateral cerebellar relative enlargement (Smaers et al., 2018). The elephant cerebellum is specialized such that it has increased neurons relative to the cerebral cortex [97.five% of the 257 billion neurons in the elephant brain are institute in the cerebellum (Herculano-Houzel et al., 2014)], and the neurons are packed more compactly than in other afrotherians (Herculano-Houzel et al., 2014).

Cortical pyramidal neuron morphology also differs betwixt humans and elephants. Human neurons have basal dendritic copse with a greater number of short branches and a vertical apical dendrite, whereas elephants appear to take longer basal dendritic segments and a 5-shaped bifurcating apical dendritic arrangement (Jacobs et al., 2011). This suggests potential differences in cortical data processing, possibly what allows elephants to accept such an extraordinary long-term, spatiotemporal, and social retention abilities (Hart and Hart, 2010).

In this regard, elephants announced to be quite attractive in the study of Advertizing and neurodegeneration. As alluded to before, families with older-aged matriarchs are more successful than families with young matriarchs considering they rely on the matriarch's ability to remember critical spatiotemporal and social data. Thus, it is possible that elephants evolved protective mechanisms to slow neurodegeneration. To our knowledge, however, no published reports address whether elephants develop neuropathologic changes similar to AD or related dementias or fifty-fifty the amount of neurodegeneration that occurs with normal aging in the absence of disease. Nosotros have therefore begun to examine and quantify historic period-related brain changes in elephants.

In our preliminary piece of work, nosotros sampled brain tissue from the prefrontal cortex of a 51-year-old female Asian zoo elephant for immunohistochemistry and immunofluorescence. The tissue was stained with ionized bounden adaptor molecule-1 (Iba-1), a calcium binding protein specific to microglia and macrophages to detect any differences in microglia morphology. Microglia tin clump together and change shape to become less ramified when activated in response to neurodegeneration (Hickman et al., 2018). In this specimen, the microglia showed no activated forms and were evenly distributed, indicating a normal land (Figure 1A). CP13, a phospho-tau antibody that stains against the Serine 202 epitope, was applied to this specimen as well. Tau accumulates in dying neurons and can be found in pathological structures such every bit neurofibrillary tangles and neuritic clusters in cases of neurodegeneration, including AD (Spillantini and Goedert, 2013). This specimen did not evidence any neurofibrillary tangles or neuritic clusters, however, some neurons located at the lower margin of the cortical layer 3 stained positively for tau, as did some pretangles in layer II (Figure 1B). This distribution is like to what would be expected in a center-aged human, as age-related tau aggregating begins in layers Two and Iii and progresses towards the deeper layers as neurodegeneration progresses (Moloney et al., 2021). The tissue was also stained with a combination of CP13 and glial fibrillary acidic protein (GFAP) using immunofluorescence. GFAP is expressed by astrocytes and the combination of activated astrocytes and tau-stained neurons is an indicator of neurodegeneration. In this specimen in that location were no activated astrocyte forms and no clumping around the tau-positive neurons. The tau "speckling" throughout the cortex (Figures 1B–F) may reflect axonal damage, or information technology may exist a species-specific artifact. It could also be representative of early crumbling, and some like (admitting less widespread) patterns appear in early-aging humans (Giannakopoulos et al., 2007; Tsartsalis et al., 2018). Investigations regarding signs of neurodegeneration are ongoing in other elephant specimens and species for a meliorate understanding of how the elephant brain changes with age.

FIGURE 1. Microglia and phospho-tau detected in brain tissue collected from the cortex of a 51-yr-old female Asian zoo elephant (Elephas maximus). Tissue stained using immunohistochemistry and counterstained with cresyl violet, (A) IBA1 (brown, ane:i,000, Fujifilm, 019–19,741), (B–D) CP13 (brown, ane:1,000, Gift from Dr. P. Davies). Images (A–D) were taken on an Axiophot brightfield microscope (Carl Zeiss Microscopy, Jena, Germany), with a 10x/0.32 Programme-Apochromat objective. (E–F) Tissue was stained with CP13 (carmine) and GFAP (light-green, 1:1,000, Abcam., ab68428) using immunofluorescence (annotation that blood vessels announced in green due to autofluorescence). Images (E–F) were taken on a CLSM 780 confocal microscope (Carl Zeiss Microscopy, Jena, Germany), using a 20x/0.8 DICII objective and DPSS 561–10 diode and Argon lasers at excitation wavelengths of 555 and 488 nm. Confocal stacks in layers Two and III of the cerebral cortex were imaged at 512 × 512 pixel resolution with a z-step of 1 µm for a pinhole setting of 1 Airy unit. Images are presented as maximum intensity projections of the Z-stack, made using ZenBlue (version 3.3, Carl Zeiss Microscopy, Jena, Germany). All calibration bars are 50 μm. In (A), microglia are evenly distributed and ramified without any activated (ameboid) forms. In (B, C), neurons stained with tau were establish in layers III and 2, respectively. In (D) tau "speckling" is visible in brown throughout layer 3, and it is as well visible in (Eastward–F) in red. Images (Eastward–F) show tau-positive neurons (thick arrowheads), and fibrils in red, and astrocytes in green (every bit well as autofluorescent claret vessels which are much thicker). Astrocytic stop anxiety are visible around some blood vessels (sparse arrows). In (F), astrocytes are indicated with stars, note their presence around the tau-positive neuron.

Neurofilament light (NfL) is a highly phosphorylated neuronal structural protein that upon neuro-axonal damage is released into the extracellular space, and subsequently into the cerebrospinal fluid and blood (Holt-Lunstad et al., 2010). Numerous reports take been fabricated of the association between serum and plasma NfL and the severity of acute central nervous system injury, as well as the presence and state of neurodegenerative disease, including AD in humans (Preische et al., 2019; Ashton et al., 2019), AD rodent models (Bacioglu et al., 2016; Andersson et al., 2020), and cognitive dysfunction in dogs (Panek et al., 2020). To our noesis nosotros are the start to measure NfL, or whatever neurodegenerative biomarker, in elephants. We measured serum NfL in 21 zoo Asian elephants (xx females, 1 male; 39.half dozen ± 16.one years of age, range 9–72 years of historic period) and plasma NfL in 9 zoo Asian elephants (7 females, 2 males; 33.2 ± 11.3 years of age, range 13–47 years of age). NfL was analyzed using the Simoa NF-light digital immunoassay (103,186, Quanterix, Billerica, MA). Serum and plasma NfL concentrations averaged 5.6 ± iii.3 and 3.2 ± 2.vii pg/ml, respectively (Figures 2A,B). In i elephant, for which we had repeated serum samples collected at ages 45, 65, 68, and 72 years (Figure 2A), we did not observe a general increase in NfL concentrations over time. Using R statistical software (R version, 3.5.2), based on a linear mixed model for the serum samples and a linear regression model for the plasma samples, we did not observe a pregnant relationship between NfL concentrations and age (p = 0.275; 0.341, respectively; significance level was determined at p < 0.05, ii-tailed). It is difficult to directly compare blood NfL concentrations across species every bit peripheral factors, such equally body mass index, which can affect blood volume and reduce NfL levels, and kidney function, which affects protein clearance, can differ across species. Regardless, NfL concentrations obtained from zoo Asian elephants in either plasma or serum are lower than humans [due east.g., run across (Khalil et al., 2020)] and dogs (Panek et al., 2020). Further data are needed to decide whether elephants are protected to a certain degree against neurodegeneration.

Figure 2. (A) Serum and (B) plasma NfL concentrations in zoo Asian elephants (Elephas maximus, due north = 21; northward = ix, respectively). The four chocolate-brown data points represent samples collected from the same elephant.

Determination

Despite the phylogenetic altitude between elephants and humans, convergence in the evolution of longevity, sociality, knowledge, and retention makes elephants an intriguing species for comparative investigation. Yet elephants have largely been overlooked as an animal model that could shed light on the diseases of aging, including cancer, Advertisement, and comorbidities associated with adverse early life experiences. Developing these resources offers slap-up potential for future research. Comprehensive life history and medical records be for elephants living under human being care, either in zoological institutions or in semi-captive atmospheric condition in range countries [e.g., records for ∼nine,600 Myanmar timber elephants captured or built-in after 1875 (Mar et al., 2001)]. This allows for retrospective analyses and aligning for differences in life experiences and health status. An intriguing opportunity too exists to compare species living in different environments, e.g., convict versus semi-captive versus wild populations. Zoological institutions are not as controlled like a traditional laboratory setting, yet they are more artificial than in the wild. Semi-captive populations fall in the middle, such that semi-captive elephants take access to veterinarian care and diet supplementation but can also roam and interact with wild elephant herds. These differences in environment and social access allow for a range of comparative studies inside species to examine the possible furnishings of external factors on the biology of crumbling. Study of elephants offers a novel and valuable perspective to aging inquiry.

Author Contributions

DC conceived of the piece of work and review. CS contributed tissue samples. NA and PH analyzed and interpreted immunohistology. MM contributed to NfL estimation. DC drafted the review. All authors participated in editing and writing the review.

Funding

This piece of work was supported in office by the National Institute on Aging (grant number P30 AG050886 to SA and DC) and Indiana Academy Plant for Avant-garde Study (to DC).

Conflict of Interest

The authors declare that the enquiry was conducted in the absence of whatever commercial or fiscal relationships that could be construed every bit a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Whatsoever product that may be evaluated in this article, or claim that may exist made by its manufacturer, is non guaranteed or endorsed by the publisher.

Acknowledgments

We thank Merina Varghese and Nicholas Grimaldi for assistance with immunohistochemistry and immunofluorescence. We want to thank Jennifer Holmes from Medical Editing Services for language editing, and Janine Brown for her constructive comments on an earlier draft of this manuscript. We give thanks M. Noonan of the Buffalo Zoo for the donation of the elephant encephalon sample. The authors as well sincerely thank the post-obit zoos for providing serum and/or plasma samples: African King of beasts Safari, Cincinnati Zoo and Botanical Garden, Columbus Zoo and Aquarium, Fort Worth Zoo, Little Rock Zoo, National Zoo, Oklahoma City Zoo, Oregon Zoo, Santa Barbara Zoo, and Saint Louis Zoo.

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Source: https://www.frontiersin.org/articles/10.3389/fragi.2021.726714/full

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