Loss of flavin adenine dinucleotide (FAD) impairs sperm function and male reproductive advantage in C. elegans

Exposure to environmental stress is clinically established to influence male reproductive health, but the impact of normal cellular metabolism on sperm quality is less well-defined. Here we show that impaired mitochondrial proline catabolism, reduces energy-storing flavin adenine dinucleotide (FAD) levels, alters mitochondrial dynamics toward fusion, and leads to age-related loss of sperm quality (size and activity), which diminishes competitive fitness of the animal. Loss of the 1-pyrroline-5-carboxylate dehydrogenase enzyme alh-6 that catalyzes the second step in mitochondrial proline catabolism leads to premature male reproductive senescence. Reducing the expression of the proline catabolism enzyme alh-6 or FAD biosynthesis pathway genes in the germline is sufficient to recapitulate the sperm-related phenotypes observed in alh-6 loss-of-function mutants. These sperm-specific defects are suppressed by feeding diets that restore FAD levels. Our results define a cell autonomous role for mitochondrial proline catabolism and FAD homeostasis on sperm function and specify strategies to pharmacologically reverse these defects.

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Loss of flavin adenine dinucleotide (FAD) impairs sperm function and male reproductive advantage in C. elegans

10.1101/456863 ◽

2018 ◽

Author(s):

Chia-An Yen ◽

Dana L. Ruter ◽

Christian D. Turner ◽

Shanshan Pang ◽

Sean P. Curran

Keyword(s):

Flavin Adenine Dinucleotide ◽

Sperm Quality ◽

Mitochondrial Dynamics ◽

Sperm Function ◽

Loss Of Function ◽

C Elegans ◽

Age Related ◽

Proline Catabolism ◽

A Cell ◽

The Impact

ABSTRACTExposure to environmental stress is clinically established to influence male reproductive health, but the impact of normal cellular metabolism on sperm quality is less well-defined. Here we show that impaired mitochondrial proline catabolism, reduces energy-storing flavin adenine dinucleotide (FAD) levels, alters mitochondrial dynamics toward fusion, and leads to age-related loss of sperm quality (size and activity), which reduces competitive fitness. Loss of the 1-pyrroline-5-carboxylate dehydrogenase enzyme alh-6 that catalyzes the second step in mitochondrial proline catabolism, leads to premature male reproductive senescence. Reducing the expression of the proline catabolism enzyme alh-6 or FAD biosynthesis pathway genes in the germline is sufficient to recapitulate the sperm-related phenotypes observed in alh-6 loss-of-function mutants. These sperm-specific defects are suppressed by feeding diets that restore FAD levels. Our results define a cell autonomous role for mitochondrial proline catabolism and FAD homeostasis on sperm function and specify strategies to pharmacologically reverse these defects.

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Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

Nature Communications ◽

10.1038/s41467-020-20269-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Mercedes M. Pérez-Jiménez ◽

José M. Monje-Moreno ◽

Ana María Brokate-Llanos ◽

Mónica Venegas-Calerón ◽

Alicia Sánchez-García ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Caenorhabditis Elegans ◽

Protein Aggregation ◽

Steroid Hormones ◽

Sensory Neurons ◽

Environmental Cues ◽

Steroid Sulfatase ◽

Loss Of Function ◽

C Elegans ◽

Age Related

AbstractAging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

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Molecular pathogenesis of progression to myeloid leukemia from TET-insufficient status

Blood Advances ◽

10.1182/bloodadvances.2019001324 ◽

2020 ◽

Vol 4 (5) ◽

pp. 845-854 ◽

Cited By ~ 3

Author(s):

Raksha Shrestha ◽

Mamiko Sakata-Yanagimoto ◽

Koichiro Maie ◽

Motohiko Oshima ◽

Masatomo Ishihara ◽

...

Keyword(s):

Median Survival ◽

Myeloid Leukemia ◽

Recurrent Events ◽

Loss Of Function ◽

Genetic Event ◽

Hematopoietic Stem ◽

Age Related ◽

Whole Exome ◽

Recurrent Mutations ◽

The Impact

Abstract Loss-of-function mutations in ten-eleven translocation-2 (TET2) are recurrent events in acute myeloid leukemia (AML) as well as in preleukemic hematopoietic stem cells (HSCs) of age-related clonal hematopoiesis. TET3 mutations are infrequent in AML, but the level of TET3 expression in HSCs has been found to decline with age. We examined the impact of gradual decrease of TET function in AML development by generating mice with Tet deficiency at various degrees. Tet2f/f and Tet3f/f mice were crossed with mice expressing Mx1-Cre to generate Tet2f/wtTet3f/fMx-Cre+ (T2ΔT3), Tet2f/fTet3f/wtMx-Cre+ (ΔT2T3), and Tet2f/fTet3f/fMx-Cre+ (ΔT2ΔT3) mice. All ΔT2ΔT3 mice died of aggressive AML at a median survival of 10.7 weeks. By comparison, T2ΔT3 and ΔT2T3 mice developed AML at longer latencies, with a median survival of ∼27 weeks. Remarkably, all 9 T2ΔT3 and 8 ΔT2T3 mice with AML showed inactivation of the remaining nontargeted Tet2 or Tet3 allele, respectively, owing to exonic loss in either gene or stop-gain mutations in Tet3. Recurrent mutations other than Tet3 were not noted in any mice by whole-exome sequencing. Spontaneous inactivation of residual Tet2 or Tet3 alleles is a recurrent genetic event during the development of AML with Tet insufficiency.

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Genetic variation in ALDH4A1 predicts muscle health over the lifespan and across species

10.1101/2021.09.08.459547 ◽

2021 ◽

Author(s):

Osvaldo Villa ◽

Nicole L. Stuhr ◽

Chia-An Yen ◽

Eileen M. Crimmins ◽

Thalida Em Arpawong ◽

...

Keyword(s):

Stress Responses ◽

Predictive Biomarker ◽

Loss Of Function ◽

C Elegans ◽

Muscle Aging ◽

Age Related ◽

The Us ◽

Muscle Health ◽

Human Participants ◽

Long Term Impact

Environmental stress can negatively impact organismal aging, however, the long-term impact of endogenously derived reactive oxygen species from normal cellular metabolism remains less clear. Here we define the evolutionarily conserved mitochondrial enzyme ALH-6/ALDH4A1 as a biomarker for age-related changes in muscle health by combining C. elegans genetics and a gene-wide association study (GeneWAS) from aged human participants of the US Health and Retirement Study (HRS)1–4. In a screen for mutations that activate SKN-1-dependent oxidative stress responses in the muscle of C. elegans5–7, we identified 96 independent genetic mutants harboring loss-of-function alleles of alh-6, exclusively. These genetic mutations map across the ALH-6 polypeptide, which lead to age-dependent loss of muscle health. Intriguingly, genetic variants in ALDH4A1 differentially impact age-related muscle function in humans. Taken together, our work uncovers mitochondrial alh-6/ALDH4A1 as a critical component of normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.

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Angptl2 is a Marker of Cellular Senescence: The Physiological and Pathophysiological Impact of Angptl2-Related Senescence

International Journal of Molecular Sciences ◽

10.3390/ijms222212232 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12232

Author(s):

Nathalie Thorin-Trescases ◽

Pauline Labbé ◽

Pauline Mury ◽

Mélanie Lambert ◽

Eric Thorin

Keyword(s):

Cell Fate ◽

Cellular Senescence ◽

Cellular Response ◽

Inflammatory Diseases ◽

Age Related ◽

A Cell ◽

Future Work ◽

The Impact

Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors and metalloproteinases, with autocrine and paracrine activities. Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in which context angptl2 was identified as a SASP factor, describe the experimental evidence showing that angptl2 is a marker of senescence in vitro and in vivo, and discuss the impact of angptl2-related senescence in both physiological and pathological conditions. Future work is needed to demonstrate whether the senescence marker angptl2 is a potential clinical biomarker of age-related diseases.

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Hallmarks of Testicular Aging: The Challenge of Anti-Inflammatory and Antioxidant Therapies Using Natural and/or Pharmacological Compounds to Improve the Physiopathological Status of the Aged Male Gonad

Cells ◽

10.3390/cells10113114 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3114

Author(s):

María Eugenia Matzkin ◽

Ricardo Saúl Calandra ◽

Soledad Paola Rossi ◽

Andrzej Bartke ◽

Mónica Beatriz Frungieri

Keyword(s):

Molecular Mechanisms ◽

Current Knowledge ◽

Sperm Quality ◽

Contributing Factors ◽

Sexual Hormones ◽

Age Related ◽

Anti Inflammatory ◽

Inflammatory Molecules ◽

The Impact ◽

Testicular Aging

The evolutionary theory of aging supports a trade-off relationship between reproduction and aging. Aging of the male reproductive system primarily affects the testes, leading to a decrease in the levels of sexual hormones, alterations in sperm quality and production, and a decline in fertility that does not necessarily involve a complete cessation of spermatogenesis. Inflammation, oxidation, and apoptosis are events considered as predictors of pathogenesis and the development of age-related diseases that are frequently observed in aged testes. Although the molecular mechanisms are still poorly understood, accumulating evidence points toward pro-inflammatory molecules and reactive oxygen species as primary contributing factors for testicular aging. However, the real impact of aging-related testicular alterations on fertility, reproductive health, and life span is far from being fully revealed. This work discusses the current knowledge on the impact of aging in the testis, particularly of aging-related dysregulated inflammation and oxidative damage on the functioning of its different cell populations. More interestingly, this review covers the potential benefits of anti-aging interventions and therapies using either pharmacological compounds (such as non-selective non-steroidal anti-inflammatory medication) or more natural alternatives (such as various nutraceuticals or even probiotics) that exhibit anti-inflammatory, antioxidant, and anti-apoptotic properties. Some of these are currently being investigated or are already in clinical use to delay or prevent testicular aging.

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Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

10.1101/541730 ◽

2019 ◽

Author(s):

Mercedes M. Pérez-Jiménez ◽

Paula Sansigre ◽

Amador Valladares ◽

Mónica Venegas-Calerón ◽

Alicia Sánchez-García ◽

...

Keyword(s):

Alzheimer Disease ◽

Drug Treatment ◽

Steroid Hormones ◽

Sensory Neurons ◽

Environmental Cues ◽

Steroid Sulfatase ◽

Loss Of Function ◽

C Elegans ◽

Age Related ◽

Signalling Process

Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity by a still not fully understood mechanism. We find that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones and increases longevity. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) and is not additive to the longevity of germline-less mutants. Noteworthy, sul-2 mutations do not affect fertility. Thus, STS inactivation affects the germline signalling process regulating longevity. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of germline longevity by environmental cues. We also demonstrate that treatment with the specific STS inhibitor STX64, reproduces the longevity phenotype of sul-2 mutants. Remarkably, STS inhibition by either mutation or drug treatment ameliorates protein aggregation diseases in C. elegans models of Parkinson, Huntington and Alzheimer, as well as Alzheimer disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors for the treatment of aging and aging related diseases.

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ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1922342117 ◽

2020 ◽

Vol 117 (49) ◽

pp. 31198-31207

Author(s):

Stephanie Vrijsen ◽

Laura Besora-Casals ◽

Sarah van Veen ◽

Jeffrey Zielich ◽

Chris Van den Haute ◽

...

Keyword(s):

Oxidative Stress ◽

Stress Response ◽

Antioxidant Properties ◽

Loss Of Function ◽

Mitochondrial Oxidative Stress ◽

C Elegans ◽

Polyamine Transport ◽

Exogenous Spermine ◽

The Impact

Recessive loss-of-function mutations inATP13A2(PARK9) are associated with a spectrum of neurodegenerative disorders, including Parkinson’s disease (PD). We recently revealed that the late endo-lysosomal transporter ATP13A2 pumps polyamines like spermine into the cytosol, whereas ATP13A2 dysfunction causes lysosomal polyamine accumulation and rupture. Here, we investigate how ATP13A2 provides protection against mitochondrial toxins such as rotenone, an environmental PD risk factor. Rotenone promoted mitochondrial-generated superoxide (MitoROS), which was exacerbated by ATP13A2 deficiency in SH-SY5Y cells and patient-derived fibroblasts, disturbing mitochondrial functionality and inducing toxicity and cell death. Moreover, ATP13A2 knockdown induced an ATF4-CHOP-dependent stress response following rotenone exposure. MitoROS and ATF4-CHOP were blocked by MitoTEMPO, a mitochondrial antioxidant, suggesting that the impact of ATP13A2 on MitoROS may relate to the antioxidant properties of spermine. Pharmacological inhibition of intracellular polyamine synthesis with α-difluoromethylornithine (DFMO) also increased MitoROS and ATF4 when ATP13A2 was deficient. The polyamine transport activity of ATP13A2 was required for lowering rotenone/DFMO-induced MitoROS, whereas exogenous spermine quenched rotenone-induced MitoROS via ATP13A2. Interestingly, fluorescently labeled spermine uptake in the mitochondria dropped as a consequence of ATP13A2 transport deficiency. Our cellular observations were recapitulated in vivo, in aCaenorhabditis elegansstrain deficient in the ATP13A2 orthologcatp-6. These animals exhibited a basal elevated MitoROS level, mitochondrial dysfunction, and enhanced stress response regulated byatfs-1, theC. elegansortholog of ATF4, causing hypersensitivity to rotenone, which was reversible with MitoTEMPO. Together, our study reveals a conserved cell protective pathway that counters mitochondrial oxidative stress via ATP13A2-mediated lysosomal spermine export.

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Trigonelline Extends the Lifespan of C. Elegans and Delays the Progression of Age-Related Diseases by Activating AMPK, DAF-16, and HSF-1

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/7656834 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Wen-Yu Zeng ◽

Lin Tan ◽

Cong Han ◽

Zhuo-Ya Zheng ◽

Gui-Sheng Wu ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Neurodegenerative Diseases ◽

Stress Resistance ◽

Aging Effect ◽

Loss Of Function ◽

Asian Countries ◽

C Elegans ◽

Age Related ◽

Anti Oxidant ◽

Pathogenic Effects

Trigonelline is the main alkaloid with bioactivity presented in fenugreek, which was used in traditional medicine in Asian countries for centuries. It is reported that trigonelline has anti-inflammatory, anti-oxidant, and anti-pathogenic effects. We are wondering whether trigonelline have anti-aging effect. We found that 50 μM of trigonelline had the best anti-aging activity and could prolong the lifespan of Caenorhabditis elegans (C. elegans) by about 17.9%. Trigonelline can enhance the oxidative, heat, and pathogenic stress resistance of C. elegans. Trigonelline could also delay the development of neurodegenerative diseases, such as AD, PD, and HD, in models of C. elegans. Trigonelline could not prolong the lifespan of long-lived worms with loss-of-function mutations in genes regulating energy and nutrition, such as clk-1, isp-1, eat-2, and rsks-1. Trigonelline requires daf-16, hsf-1, and aak-2 to extend the lifespan of C. elegans. Trigonelline can also up-regulate the expression of daf-16 and hsf-1 targeted downstream genes, such as sod-3, gst-4, hsp-16.1, and hsp-12.6. Our results can be the basis for developing trigonelline-rich products with health benefits, as well as for further research on the pharmacological usage of trigonelline.

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Fission and PINK-1-mediated mitophagy are required for Insulin/IGF-1 signaling mutant reproductive longevity

10.1101/2021.08.16.456566 ◽

2021 ◽

Author(s):

Vanessa Cota ◽

Coleen T Murphy

Keyword(s):

Mitochondrial Dynamics ◽

Oocyte Quality ◽

Mitochondrial Morphology ◽

Reproductive Aging ◽

Human Aging ◽

Wild Type ◽

C Elegans ◽

Age Related ◽

Receptor Mutant

Women′s reproductive cessation is the earliest sign of human aging and is caused by decreasing oocyte quality. Similarly, C. elegans′ reproduction declines with age and is caused by oocyte quality decline. Aberrant mitochondrial dynamics are a hallmark of age-related dysfunction, but the role of mitochondrial morphology in reproductive aging is largely unknown. We examined the requirements for mitochondrial fusion and fission in oocytes of both wild-type worms and the long-lived, long-reproducing insulin-like receptor mutant daf-2. We find that normal reproduction requires both fusion and fission. By contrast, daf-2 mutants require fission, but not fusion, for reproductive span extension. daf-2 mutant oocytes′ mitochondria are punctate (fissioned) and may be primed for mitophagy, as loss of the mitophagy regulator PINK-1 shortens daf-2′s reproductive span. Our data suggest that daf-2 maintain oocyte mitochondria quality with age via a shift toward punctate mitochondrial morphology and mitophagy to extend reproductive longevity.

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