The role of phagocytic cells in aging: insights from vertebrate and invertebrate models.

While the main role of phagocytic scavenger cells consists of the neutralization and elimination of pathogens, they also keep the body fluids clean by taking up and breaking down waste material. Since a build-up of waste is thought to contribute to the aging process, these cells become particularly pertinent in the research field of aging. Nevertheless, a direct link between their scavenging functions and the aging process has yet to be established. Integrative approaches involving various model organisms hold promise to elucidate this potential, but are lagging behind since the diversity and evolutionary relationship of these cells across animal species remain unclear. In this perspective, we review the current knowledge associating phagocytic scavenger cells with aging in vertebrate and invertebrate animals, as well as put forward important questions for further exploration. Additionally, we highlight future challenges and propose a constructive approach for tackling them.

Endocytic coelomocytes are required for lifespan extension by axenic dietary restriction.

A rather peculiar but very potent means of achieving longevity is through axenic dietary restriction (ADR), where animals feed on (semi-)defined culture medium in absence of any other lifeform. The little knowledge we already have on ADR is mainly derived from studies using the model organism Caenorhabditis elegans, where ADR more than doubles organismal lifespan. What is underlying this extreme longevity so far remains enigmatic, as ADR seems distinct from other forms of DR and bypasses well-known longevity factors. We here focus first on CUP-4, a protein present in the coelomocytes, which are endocytic cells with a presumed immune function. Our results show that loss of cup-4 or of the coelomocytes affects ADR-mediated longevity to a similar extent. As the coelomocytes have been suggested to have an immune function, we then investigated different central players of innate immune signalling, but could prove no causal links with axenic lifespan extension. We propose that future research focuses further on the role of the coelomocytes in endocytosis and recycling in the context of longevity.

Adult-restricted gene knock-down reveals candidates that affect locomotive healthspan in C. elegans.

Understanding how we can age healthily is a challenge at the heart of biogerontological interest. Whereas myriad genes are known to affect the lifespan of model organisms, effects of such interventions on healthspan-the period of life where an animal is considered healthy, rather than merely alive-are less clear. To understand relationships between life- and healthspan, in recent years several platforms were developed with the purpose of assessing both readouts simultaneously. We here relied on one such platform, the WorMotel, to study effects of adulthood-restricted knock-down of 130 Caenorhabditis elegans genes on the locomotive health of the animals along their lifespans. We found that knock-down of six genes affected healthspan while lifespan remained unchanged. For two of these, F26A3.4 and chn-1, knock-down resulted in an improvement of healthspan. In follow-up experiments we showed that knockdown of F26A3.4 indeed improves locomotive health and muscle structure at old age.

Conditional gene expression in invertebrate animal models.

A mechanistic understanding of biology requires appreciating spatiotemporal aspects of gene expression and its functional implications. Conditional expression allows for (ir)reversible switching of genes on or off, with the potential of spatial and/or temporal control. This provides a valuable complement to the more often used constitutive gene (in)activation through mutagenesis, providing tools to answer a wider array of research questions across biological disciplines. Spatial and/or temporal control are granted primarily by (combinations of) specific promoters, temperature regimens, compound addition, or illumination. The use of such genetic tool kits is particularly widespread in invertebrate animal models because they can be applied to study biological processes in short time frames and on large scales, using organisms amenable to easy genetic manipulation. Recent years witnessed an exciting expansion and optimization of such tools, of which we provide a comprehensive overview and discussion regarding their use in invertebrates. The mechanism, applicability, benefits, and drawbacks of each of the systems, as well as further developments to be expected in the foreseeable future, are highlighted.