A large-scale international study led by the University of Exeter Medical School has discovered new genes linked to parents’ lifespan – which could one day be targeted to help prolong human life.
How long we live is determined by a range of factors including our lifestyle and how well we treat factors including blood pressure and cholesterol from midlife. However, genetics, and how long our parental relatives lived, also plays a role.
Now, the number of genes we know influence lifespan has expanded, potentially paving the way to new therapeutic targets to prolong life.
The study, funded by the Medical Research Council and conducted in collaboration with a number of US universities, undertook a genome-wide search for variants influencing how long participants’ parents lived. The team studied 389,166 volunteers who took part in the UK Biobank, with confirmation in the US Health and Retirement Study and the Wisconsin Longitudinal Study. The DNA samples from the volunteers carry the genetics of their biological parents, so provide a practical way of studying exceptionally long lifespans.
Eight genetic variants had already been linked for lifespan, mainly involved in heart disease and dementia. The latest study has expanded this to 25 genes in all, with some specific to mothers’ or fathers’ lifespan separately.
Dr Luke Pilling, who undertook most of analyses said: “We have identified new pathways that contribute to survival, as well as confirming others. These targets, including inflammatory and cardiovascular pathways, offer potentially modifiable targets to reduce risk of an earlier death and improve health.”
Genes involved in senescence, the ‘frozen’ state that cells enter into after being damaged, played an important role in longevity. Drugs targeting senescence have already been shown to extend life in laboratory animals.
Genes related to inflammation and auto-immunity-related genes were also prominent, opening up the possibility that precision anti-inflammatory treatments may one day be helpful in extending life.
The results confirm that many genetic variants combine to influence human lifespan: no single gene variant was found to be responsible.
The study found evidence to suggest that the genetic variants for average lifespan also influence exceptionally long life expectancy. A genetic risk score combining the top ten variants was statistically associated with parents being centenarians.
Exeter Universityhttps://tinyurl.com/yakjsfoj

When researchers at the University of São Paulo (USP) in Brazil treated human melanoma cell lines with a synthetic compound similar to curcumin, one of the pigments that give turmeric (Curcuma longa) its orange colour, they identified genes with altered expression in potentially invasive tumours and malignant cells resistant to chemotherapy.
According to the scientists, if further studies confirm the importance of these genes to disease progression and increasing chemoresistance, it will be possible to explore their future use as biomarkers to assist diagnosis and even as therapeutic targets.
“Previous research by collaborators had already shown that DM-1, a compound analogous to curcumin, has anti-tumour activity at low doses. We set out to understand which genes this substance modulates and why it is toxic to melanoma but not to normal cells,” said Érica Aparecida de Oliveira, a postdoctoral scholar at USP’s School of Pharmaceutical Sciences (FCF).
As Oliveira explained, there are hundreds of papers attesting to the anti-oxidant, anti-tumoural, anti-microbial and anti-inflammatory properties of curcumin in the scientific literature. However, the therapeutic usefulness of this compound in its natural form is limited owing to poor absorption, rapid metabolization, and water insolubility. To solve this problem, scientists have developed synthetic analogues with minor structural modifications to make the molecule more stable in the organism.
DM-1 (sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate) was synthesized some years ago by José Agustín Pablo Quincoces Suárez, a professor at Bandeirantes University (UNIBAN).
“Experiments with animals conducted by collaborators showed that treatment with DM-1 can promote a reduction in tumour volume. DM-1 has also proved toxic to chemoresistant melanoma cells,” Oliveira said.
To unpack DM-1’s mechanism of action, Oliveira resorted to a toxicogenomics platform developed by the research group of FCF-USP professor Gisele Monteiro, a fellow researcher at the investigation. Such platform is comprised of a collection of 6,000 frozen yeast strains, all mutants of the species Saccharomyces cerevisiae, widely used as baker’s and brewer’s yeast.
“This yeast’s genome has 6,000 genes, and a different gene has been knocked out in each of these mutants, so we were able to study the effects of the compound in a highly specific manner, gene by gene,” Oliveira said.
The 6,000 mutant yeast strains were thawed, spread on plates with 96 small wells, and treated with DM-1. The strains that did not grow in the presence of the curcumin analogue were discarded, leaving an initial group of 211 genes that were affected by the treatment.
The next step was to filter the genes in order to identify those with homologues in the human genome since some might be associated with functions specific to yeast. The researchers came up with a second list containing 79 candidate genes, thanks to the aid from bioinformatics tools and from the expertise of Helder Nakaya , another fellow researcher and also a professor at FCF-USP.
“We then began to look at public repositories of genomic data from cancer patients, such as The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), to understand how these genes talked to each other,” Oliveira said.
The analysis showed most to be associated with cell signalling pathways that favoured tumour progression when active. Examples included the pathways mediated by mitogen-activated protein (MAP) kinase and epidermal growth factor receptor (EGFR).
The next step was to investigate which genes were important to the progression of melanoma specifically. This entailed using bioinformatics to focus on the analysis of genomic sequences from melanoma patients.
“We performed a data mining exercise to find genes with altered expression during melanoma progression,” Oliveira said. “We identified seven genes that appeared to be important, and when we looked at the public databases, we could see that the expression of these genes was indeed altered in many patients.”
In vitro tests with non-chemoresistant parent melanoma cells showed that treatment with DM-1 induced cell death, mainly because it increased expression of a gene known as TOP-1. When this gene is active, it leads to DNA transcription errors and hence causes genomic instability in cells.
In chemoresistant melanoma cells, cytotoxicity was caused mainly by increased expression of the gene ADK, which is involved in energy production for cells.
“Like curcumin, which can interact with multiple cellular targets and modulate multiple signaling pathways, DM-1 also acts in different ways to promote toxicity in both parent and drug-resistant melanoma cells,” Oliveira said.
EurekAlerthttps://tinyurl.com/ya7hhwwk

In a new study New York University College of Dentistry (NYU Dentistry) researchers investigating the catabolic effect of parathyroid hormone (PTH) in hyperparathyroidism (HPT) showed, for the first time, that monocyte chemoattractant protein-1 (MCP-1) is required for catabolic responses to PTH. HPT is a condition in which an abnormally high concentration of PTH in the blood accelerates bone loss.
The research team, led by Nicola C. Partridge, PhD, professor and chair of the Department of Basic Science and Craniofacial Biology at NYU Dentistry, had previously found that MCP-1 is important in producing an anabolic effect of PTH, in which bone formation is increased, and they wanted to know if it was also important in causing a catabolic effect, in which bone is broken down.
In the present study, the researchers focused on the role of MCP-1 in PTH-induced osteoclast formation. Osteoclasts are cells that break down the bone. Increased osteoclast formation causes bones to become thinner and weaker. The researchers recreated the hyperparathyroid state in mice by constantly elevating their hyperparathyroid levels. Over a two-week period, they continuously infused female wild-type and MCP-1 knockout mice with human PTH. They showed that the ability of PTH to increase osteoclast formation in vitro is markedly impaired in cells from MCP-1 knockout mice and concluded that MCP-1 is an important chemokine, or signalling protein, in PTH-induced osteoclast formation and bone resorption.
The findings support the possibility that MCP-1 could be a marker for how PTH works in humans with hyperparathyroidism, as elevated serum MCP-1 has been shown to be correlated with elevated serum PTH levels in women. Notably, within minutes after humans undergo parathyroid adenoma surgery, MCP-1 serum levels decrease.
Because high serum levels of MCP-1 cause the white cells and osteoclasts to be stimulated, this process could have systemic effects as well as effects on bone. “MCP-1 is a chemokine, which induces cells to move along a gradient recruiting white cells and osteoclasts in tissues,” says Dr. Partridge. “Accordingly, there could also be effects on adipose tissue, the heart, and inflammatory conditions.”
In the United States, about 1,000 people develop HPT each year, with osteoporosis the most common manifestation. According to the National Institutes of Health, there are approximately 1.5 million osteoporotic fractures in the U.S. each year that lead to half a million hospitalizations, over 800,000 emergency room encounters, more than 2,600,000 physician office visits, and the placement of nearly 180,000 individuals in nursing homes. Hip fractures are by far the most devastating type of fracture, accounting for about 300,000 hospitalizations each year. About one in five people sustaining a hip fracture ends up in a nursing home.  
NYU College of Dentistryhttps://tinyurl.com/y7nzipw9

A simple blood test that detects tumour cells circulating in the blood shows promise as a new way to predict high or low risk of a breast cancer relapse.
“Late recurrence five or more years after surgery accounts for at least one-half of recurrences of breast cancer, and there are no tests that identify who is at highest risk. We found that in women who were cancer-free five years after diagnosis, about 5 percent had a positive circulating tumour cells (CTC) test,” said lead researcher Joseph A. Sparano, MD, vice chair of the ECOG-ACRIN Cancer Research Group, Philadelphia, and associate director for clinical research at Montefiore Medical Center, Albert Einstein Cancer Center, New York.
“More importantly …”, Dr. Sparano continued, “…we also found that a positive test was associated with a 35 percent recurrence risk after two years, compared with only 2 percent for those with a negative CTC test.”
The concept is to explore the use of the CTC blood test in a new way. Currently, the test is FDA-approved for use by physicians to monitor response to treatment in patients with advanced breast, colon or prostate cancer, but not early stage cancer. A rise in the number of circulating tumour cells in the blood in patients with advanced disease may indicate trouble before it shows up on a scan. In this study, the research team evaluated this test in a different setting—individuals alive and cancer-free about five years after their diagnosis and potentially cured, but still at risk for having a recurrence of their disease.
”Our ultimate goal is to use blood tests like this to tailor treatment in a way that minimizes recurrence risk for those at high risk, and spare treatment for those at low risk who may be unlikely to benefit from it,” Dr. Sparano said. “The findings of this analysis provide strong evidence to further evaluate this new risk assessment approach using CTC and other blood-based tests in this setting”.
The test was done on a single blood sample provided by 547 breast cancer patients who had been diagnosed more than five years prior and treated as part of a large ECOG-ACRIN breast cancer treatment trial, E5103. This group of patients had stage two or three breast cancer, and the cells in their tumours were HER2-negative.
Many women in E5103 remain cancer free and are being followed for their breast cancer status as part of standard care. Dr. Sparano and colleagues set up a biobank and invited these patients to contribute additional specimens for future research into the reasons for late recurrence. The biobank was established by ECOG-ACRIN and the Coalition of Cancer Cooperative Groups with funding from the Breast Cancer Research Foundation, National Cancer Institute, and Susan G. Komen.
ECOG-ACRIN Cancer Research Grouphttps://tinyurl.com/ydgym4c3