The central role of oxidative damage, telomere attrition, mitochondrial genome damage, and epigenetic alterations in aging is well documented (1). The study of these different causes is best done through the use of model organisms as they are readily amenable to both genetic manipulation and molecular analysis. Two simple model organisms where aging is well studied are yeast (
Genetic studies in model organisms have shown that aging is regulated by a specific cluster of genes and have allowed for the analysis of the different pathways involved in physiology, signal transduction, and gene regulation (4). Of note, energy depletion (and calorie restriction) in yeast through glucose deprivation was found to extend the lifespan of mother cells (5). This is due to silencing of DNA via deacetylation of histones by silent information regulator (Sir) proteins (Fig. 1) (4). These proteins are downstream of a signaling pathway involving Sum1p that detects cellular glucose and responds by repressing key genes that promote aging (4, 6). Homologs of the Sir proteins (Sir-2.1) have also been studied in
The mouse model is also an attractive choice for aging studies. Mice have a relatively shorter lifespan and a wide array of ana-tomical and physiological characteristics that are shared with humans (14). In mice, calorie restriction similarly delays aging at least in part through SIRT1-dependent PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1α) activation (15) and SIRT1-mediated antioxidant response in mice (Fig. 1) (16). On the contrary, upregulation of insulin/IGF-1 accelerates aging and predisposes to age-related diseases (Fig. 1) (17). Mice have long telomeres and higher telomerase activity in many organs, which limits the usefulness of comparative studies with humans (14). Using telomerase-deficient mice, it has been demonstrated that telomere damage promotes age-associated decline in organ function and increased disease risk (18). Moreover, telomere dysfunction accelerates aging in mice and humans, as evidenced by the delay in aging upon experimental stimulation of telomerase in mice (1). However, exces-sive telomerase activity is a critical step for the development of human cancers. Notably, calorie restriction also attenuates aging-associated shrinkage of telomeres in mouse tissue and reduces the incidence of tumors in mice that overexpress telomerase (19). Therefore, molecular and cellular mechanisms controlling aging and aging-associated pathology are likely conserved across species.
A key principle that describes the trade-off between immortal germline and the disposable soma is Thomas Kirkwood’s disposable soma theory of aging. This theory proposes that germline immortality comes at the expense of somatic aging (Fig. 2A and 2B). Also, the removal of germline delays aging and improves somatic recovery (Fig. 2C) (20, 21). Thus, the soma is disposable and the resources are shifted to be used on reproduction, and the germline is labeled as expensive (22). While there has been work supporting this theory, another view challenged the disposable soma theory. Rather than the soma being disregarded so that more resources are focused on germline maintenance, these two components work together through common signaling pathways (22).
The disposable soma theory has been supported through a countless number of experiments using model organisms such as worms, flies, and zebrafish. In regard to
As for humans, Min
To date, significant progress has been made in understanding genetic and environmental factors of aging. Likewise, the interest in the molecular mechanisms through which the reproductive system modulates somatic aging and vice versa, have recently emerged in multiple model systems.
Likewise, the effect of germline ablation on longevity was also examined in
Other studies have focused on intermediate metabolites of the pyrimidine metabolism pathway to infer how it regulates reproductive signals involved in lifespan of
Along with lipid metabolism, autophagy is another important lifespan extension mechanism in multiple animals (Fig. 1). Specifically, in
In a study by Wei and Kenyon, the role of reactive oxygen species (ROS) and hydrogen sulfide in the longevity response to germline loss in
Prostaglandins have also been shown to be involved in longevity and lifespan determination. It was found that a relationship existed between lower, optimal body temperature, germline, and lifespan in
DAF-12 is a receptor in
Studies have shown that there is an inverse relationship between aging and GSC proliferation. As
Several studies have been done focusing on JH and its effects in different invertebrates. JH is involved in the metamorphosis of this organism by stimulating differentiation by inhibiting the morphogenesis of certain tissues (57). The researchers proposed that JH was a mediator for reproductive and longevity trade-off (25). There is also an inverse relationship on reproduction, which is caused by JH, and survival (58). This signaling pathway occurs downstream of the Insulin/IGF-1 pathway (25). JH analog (JHa) methoprene was used for selection, to mimic the effects of JH-deficiency in flies. As expected, JHa treatment increased mortality in the unselected, susceptible controls in exchange for early fertility (25). Upon successful selection, flies gained resistance to JHa, extending their lifespan by an average of 3.8 days (25). This finding was in agreement with the longer lifespan in flies without JH (25).
It is established that hormones are essential in regulating body processes, and germline aging is no exception. The anterior pituitary gland is a major organ of the endocrine system that secretes gonadotropins, such as luteinizing hormone (LH). LH plays an important role in reproductive aging in mammals (59). A preovulatory LH surge causes oocytes to be arrested during prophase I of meiosis in females. Likewise, LH also increases the survival rate of male germ cells (60). In a study by Kawamura
Mounting evidence suggests that somatic tissues play a critical role in reproductive aging and vice versa. Using animal models such as
We thank members of the Lee laboratory and ECU Reproductive Biology Interest Group (RBIG) for insightful discussions. We are also grateful to Jiwoo Lee (Hope Middle School, NC, USA) and Jiah Lee (Hope Middle School, NC, USA) for assistance with figures. This work was supported by NIA (AG060373-01) to MHL.
The authors have no conflicting interests.