Aging is associated with an impairment in stem cell function and several strategies for stem cell rejuvenation have been proposed: exercise, dietary restriction, reprogramming, senolytics, increasing autophagy, youthful blood factors exchange, and restoring cell polarity. Here, we review these strategies and their effects on rejuvenating stem cells in different tissues and underline when stem cell rejuvenation was able to improve health and lifespan.

Aging is associated with a global decline in stem cell function. To date, several strategies have been proposed to rejuvenate aged stem cells: most of these result in functional improvement of the tissue where the stem cells reside, but the impact on the lifespan of the whole organism has been less clearly established. Here, we review some of the most recent work dealing with interventions that improve the regenerative capacity of aged somatic stem cells in mammals and that might have important translational possibilities. Overall, we underscore that somatic stem cell rejuvenation represents a strategy to improve tissue homeostasis upon aging and present some recent approaches with the potential to affect health span and lifespan of the whole organism.

The long noncoding RNA TERRA controls telomere length homeostasis in human cancers with an activated alternative lengthening of telomeres (ALT) mechanism. Telomeric R-loops formed between TERRA and telomeric DNA (telR-loops) promote telomere elongation through homology-directed repair. However, if not properly regulated, TERRA and telR-loops can lead to rapid cleavage of telomeric DNA and telomere loss.

Eukaryotic telomeres are transcribed into the long noncoding RNA TERRA. A fraction of TERRA remains associated with telomeres by forming RNA:DNA hybrids dubbed telR-loops. TERRA and telR-loops are essential to promote telomere elongation in human cancer cells that maintain telomeres through a homology-directed repair pathway known as alternative lengthening of telomeres or ALT. However, TERRA and telR-loops compromise telomere integrity and cell viability if their levels are not finely tuned. The study of telomere transcription in ALT cells will enormously expand our understanding of the ALT mechanism and of how genome integrity is maintained. Moreover, telomere transcription, TERRA and telR-loops are likely to become exceptionally suited targets for the development of novel anti-cancer therapies.

Fatty acids (FAs) are critical molecules for cell growth, proliferation, and development; but are toxic to cells when present in excess. Eukaryotic cells therefore sequester FAs in organelles called lipid droplets (LDs) until needed. LD synthesis and breakdown are under precise metabolic control, and dysregulation of these pathways is linked to lipotoxicity and diseases.

Lipid droplets (LDs) are fat storage organelles that are conserved from bacteria to humans. LDs are broken down to supply cells with fatty acids (FAs) that can be used as an energy source or membrane synthesis. An overload of FAs disrupts cellular functions and causes lipotoxicity. Thus, by acting as hubs for storing excess fat, LDs prevent lipotoxicity and preserve cellular homeostasis. LD synthesis and turnover have to be precisely regulated to maintain a balanced lipid distribution and allow for cellular adaptation during stress. Here, we discuss how prolonged exposure to excess lipids affects cellular functions, and the roles of LDs in buffering cellular stress focusing on lipotoxicity.

Lipid transport is an essential process that underlies the biogenesis and expansion of organelles. Despite its basic importance, there is a dearth of assays to probe lipid exchange between organelles in vivo. Here we discuss the development of a versatile method called METALIC (Mass tagging-Enabled Tracking of Lipids in Cells), that uses enzyme-based mass tagging of lipids in conjunction with mass spectrometry to track interorganelle lipid transport inside living cells.

Lipid trafficking is critical for the biogenesis and expansion of organelle membranes. Lipid transport proteins (LTPs) have been proposed to facilitate lipid transport at contact sites between organelles. Despite the fundamental importance of LTPs in cell physiology, our knowledge on the mechanisms of interorganelle lipid distribution remains poor due to the scarcity of assays to monitor lipid flux in vivo. In this review, we highlight the recent development of a versatile method named METALIC (Mass tagging-Enabled Tracking of Lipids in Cells), which uses a combination of enzymatic mass tagging and mass spectrometry to track lipid flux between organelles inside living cells. We discuss the methodology, its distinct advantages, limitations as well as its potential to unearth the pipelines of lipid transport and LTP function in vivo.

A journey from the polished quartz lenses in the eyes of an ancient Egyptian statue of a seated scribe, through the development of microscopes and towards modern electron microscopy. Recent advances in field emission scanning electron microscopy have made it possible to expose nuclei from human cells and to focus on individual nuclear pore complexes, comparing their architectural features.

A journey from the earliest known use of lenses and magnifying glasses in ancient times, through the development of microscopes and towards modern electron microscopy techniques. The evolving technology and improved microscopes enabled the discovery of intracellular organelles, the nucleus and nuclear pore complexes (NPCs). Current advances have led to composite three-dimensional models showing NPC structure in unprecedented detail but relying on the averaging of many images. A complementary approach is field emission scanning electron microscopy providing topographic surface images that are easily and intuitively interpreted by our brain. Recent advances in this technique have made it possible to expose nuclei from human cells and to focus on individual NPCs and their architectural features.

The nucleus accumbens is key for encoding reward/aversion and associative learning, being the limbic-motor interface of the brain. This encoding occurs through activity of medium spiny neurons (MSNs) that express either dopamine receptor D1 or D2. Here, we discuss evidence supporting a complex and complementary role of D1- and D2-MSNs in encoding both appetitive and aversive cue–outcome associative learning.

The nucleus accumbens (NAc) has been considered a key brain region for encoding reward/aversion and cue–outcome associations. These processes are encoded by medium spiny neurons that express either dopamine receptor D1 (D1-MSNs) or D2 (D2-MSNs). Despite the well-established role of NAc neurons in encoding reward/aversion, the underlying processing by D1-/D2-MSNs remains largely unknown. Recent electrophysiological, optogenetic and calcium imaging studies provided insight on the complex role of D1- and D2-MSNs in these behaviours and helped to clarify their involvement in associative learning. Here, we critically discuss findings supporting an intricate and complementary role of NAc D1- and D2-MSNs in associative learning, emphasizing the need for additional studies in order to fully understand the role of these neurons in behaviour.

Dysregulation of nuclear function has been implicated in many human diseases. Thus, identifying and characterizing quality control mechanisms that regulate nuclear structure and function is essential. Herein, we discuss autophagy pathways responsible for the degradation of diverse nuclear cargoes across eukaryotic species and highlight the need for a better understanding of nuclear cargo composition and packaging mechanisms, which remain largely uncharacterized.

Due to their essential functions, dysregulation of nuclear pore complexes (NPCs) is strongly associated with numerous human diseases, including neurodegeneration and cancer. On a cellular level, longevity of scaffold nucleoporins in postmitotic cells of both C. elegans and mammals renders them vulnerable to age-related damage, which is associated with an increase in pore leakiness and accumulation of intranuclear aggregates in rat brain cells. Thus, understanding the mechanisms which underpin the homeostasis of this complex, as well as other nuclear proteins, is essential. In this review, autophagy-mediated degradation pathways governing nuclear components in yeast will be discussed, with a particular focus on NPCs. Furthermore, the various nuclear degradation mechanisms identified thus far in diverse eukaryotes will also be highlighted.

During the formation of autophagosomes, the phagophore membrane expands rapidly and is decorated by lipidated ATG8s, LC3 and GABARAP. The amphipathic helix of ATG3, the ubiquitin-like E2 enzyme, has unique properties that catalyse the conjugation of ATG8 to phosphatidylethanolamine (PE). Further membrane expansion occurs by interaction in cis when the N-terminus of the lipidated ATG8 inserts into the membrane.

Autophagy is a highly conserved intracellular pathway that is essential for survival in all eukaryotes. In healthy cells, autophagy is used to remove damaged intracellular components, which can be as simple as unfolded proteins or as complex as whole mitochondria. Once the damaged component is captured, the autophagosome engulfs it and closes, isolating the content from the cytoplasm. The autophagosome then fuses with the late endosome and/or lysosome to deliver its content to the lysosome for degradation. Formation of the autophagosome, sequestration or capture of content, and closure all require the ATG proteins, which constitute the essential core autophagy protein machinery. This brief ‘nutshell’ will highlight recent data revealing the importance of small membrane-associated domains in the ATG proteins. In particular, recent findings from two parallel studies reveal the unexpected key role of α-helical structures in the ATG8 conjugation machinery and ATG8s. These studies illustrate how unique membrane association modules can control the formation of autophagosomes.