Research Worth Sharing, December 2024 Edition

Welcome to another edition of “Research Worth Sharing” – a roundup of recent research that we’ve found interesting and which we hope might provide worthwhile insights to others as well.

Rising rates of youth-onset type 2 diabetes

Why we are interested: Insulin resistance and type 2 diabetes (T2D), in addition to their substantial negative impacts on quality of life, increase risk of all of the most deadly and debilitating chronic diseases. These effects are alarming enough in light of the relatively high prevalence (~11%) of T2D among US adults,¹ but as diabetes expert Dr. Ralph DeFronzo explained in a soon-to-be-released episode of The Drive, rates of insulin resistance and T2D are also on the rise among adolescents – who, to make matters worse, often don’t respond to existing diabetes medications as well as adults do. Thus, this 2023 review – which details more precisely the trends in T2D prevalence among adolescents – caught my attention as a follow-up to my discussion with Dr. DeFronzo, and I share it so that parents like myself might understand that T2D and its associated health complications are no longer exclusively the concerns of adults.

What they showed: This review focused on the burden of T2D among individuals under the age of 20, primarily within the US. The authors report that T2D has grown steadily more common in young people in the US since at least 2002 (the baseline for their analysis), with most recent data indicating a prevalence of approximately 0.67% among individuals between the ages of 10 and 19 and 1.04% specifically among those at the upper end of that age group (ages 15-19). These numbers might seem small when compared to prevalence in US adults, yet they represent hundreds of thousands of individuals suffering from a debilitating chronic disease formerly associated exclusively with adults. Indeed, the authors report an annual percent change in incidence of 4.8% since 2002, and note that by some estimates, prevalence will increase four-fold from 2017 to 2050. 

doi: 10.2337/dci22-0046

Extending donor organ lifetime with subzero storage systems

Why we are interested: In the United States alone, over 100,000 patients are currently on waitlists for life-saving organ transplants, yet many (5-6%) die waiting.² One of the major problems underlying the deficit in supply is the fact that organs only remain viable for a matter of hours under standard storage conditions (ranging from approximately 4 hours for hearts to <24 hours for kidneys). Extending this window would thus potentially save or improve many thousands of lives worldwide.

What they showed: A surgical and research team led by Dr. Gerald Brandacher at the Johns Hopkins School of Medicine preserved pig kidneys for up to 72 hours at subzero temperatures before successfully transplanting them into recipient pigs and confirming that they retained normal functionality. The kidney was stored at -5°C in XT-ViVo (a non-toxic preservation solution) in a TimeSeal device – both products of X-Therma, a biotechnology company that specializes in preservation of biological tissue. (X-Therma also covered Dr. Brandacher’s achievement in a recent press release.³) In their proof-of-principle report, the investigators note that all four kidneys preserved with the novel system for 72 hours exhibited normal long-term function, in contrast to two control kidneys preserved by standard procedures. Further, the team demonstrated that the system could be used for long-distance organ transport, as a kidney remained viable after multiple transatlantic trips over the course of 48 hours. Together, these developments offer hope that more widespread use of this storage system may help overcome some of the current barriers to meeting the high demand for donor organs. 

doi: 10.1097/01.tp.0001066636.10142.f4

Mortality risk after ovary removal among women at high risk for breast and ovarian cancer

Why we are interested: Certain mutations in the BRCA1 and BRCA2 significantly increase risk of breast and ovarian cancer. Some of these mutations are quite common, and thus, any data that might inform efforts to counteract this added risk are worthy of attention. Yet I’ve also chosen to highlight this study for another reason – it serves as an excellent illustration of the power of two key tenets of “Medicine 3.0”: the importance of proactive preventative measures and the need for personalization.

What they showed: In this longitudinal cohort study, investigators evaluated data from 4,332 women with BRCA1 or BRCA2 mutations but no prior history of cancer (mean age: 46.2 years). Approximately two-thirds of these women elected to undergo preventative bilateral oophorectomy (removal of both ovaries). After a mean follow-up of 9.0 years, women who had undergone this procedure were reportedly 68% less likely to have died from any cause than their counterparts who had not had oophorectomies (age-adjusted HR: 0.32; 95% CI: 0.24-0.42; P<0.001). The risk reduction was stronger among those with BRCA1 mutations (age-adjusted HR: 0.28; 95% CI: 0.20-0.38; P<0.001) than those with BRCA2 mutations (age-adjusted HR: 0.43; 95% CI: 0.22-0.90; P=0.03).

Removal of the ovaries results in early menopause, which typically increases risk for other conditions such as sarcopenia and heart disease. Thus, the reduction in all-cause mortality with oophorectomy observed in this study is noteworthy because it indicates that for women at high genetic risk for breast and ovarian cancer, the benefits of preventative bilateral oophorectomy outweigh the risks incurred by the procedure, which likely would not be the case for women at normal risk. In other words, this study exemplifies the importance of individualized risk assessments and preventative measures as a means of extending lifespan and healthspan.

doi: 10.1001/jamaoncol.2023.6937

Exploring the “dark genome” as a target for therapeutics

Why we are interested: Genes – the sections of DNA that code for proteins – make up only a tiny percentage of our genome. The rest, which is referred to as the “dark genome,” is poorly understood and typically ignored with respect to potential clinical applications. Yet the dark genome is known to include dormant virus-like genetic elements that can, as mounting evidence suggests, reactivate and promote inflammation and genomic instability – which in turn can drive development of metabolic dysfunction, cancer, and other chronic diseases.

What they showed: In this Nature Biotechnology editorial, author Michael Eisenstein shines light on a shift in the biotech industry toward greater interest in the dark genome and virus-like genetic elements as possible therapeutic targets. For instance, a subset of these genetic viruses known as human endogenous retroviruses (HERVs) appear to be reactivated with aging, infections, and certain tumors. The viral proteins encoded by these normally silent HERVs mark cells as abnormal, which can lead to a potent immune response. In the context of cancer, this may aid the immune system in identifying and destroying cancer cells, and biotech companies are therefore investigating how HERVs might be leveraged in enhancing cancer immunotherapy. On the other hand, when reactivation of virus-like elements occurs in normal cells, it can lead to inflammatory conditions and tissue damage (e.g., reactivation in neurons may lead to the immune system attacking neural tissue). Thus, companies are also devoting resources toward understanding how these genetic elements might contribute to neurological and neuromuscular disorders, and clinical trials are currently underway to test whether therapeutics intended to target HERVs and other genetic viruses might slow the course of diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

doi: 10.1038/s41587-024-02215-1

Vascular dysfunction and age-related losses in exercise tolerance

Why we are interested: We’ve all heard (or experienced) how advancing age is accompanied by declines in physical function. Eventually, this decline can impede everyday activities and negatively impact both quality and duration of life. Therefore, understanding the mechanisms by which we lose our physical abilities is vital for determining how to slow or prevent such a downward trend. Part of the problem stems from the fact that, as we age, we lose muscle mass and strength. But is there more to the story?

What they showed: The researchers involved in this study sought to determine whether losses in exercise tolerance (as assessed by critical power, or the maximum effort one can sustain without reaching a point of fatigue) were entirely attributable to losses in muscle mass or if other factors were at play. Twenty healthy, active adults (50% female), split between a young group (age: 24.4±4 years) and older group (age: 63.1±3 years), underwent five consecutive days of exercise testing to assess various metrics of fitness, body composition, and other physiological parameters.

As expected, the older group demonstrated 32% lower absolute critical power than the young group, but more surprisingly, the disparity persisted after normalizing results for lean mass, with the older group exhibiting 30% lower critical power than the younger group. These findings indicate that losses in muscle mass do not account for most of the difference in critical power between age groups. By examining additional metrics, the investigators concluded that the decline in power was instead related primarily to impaired blood flow and vascular conductance to the working muscles during exercise. Though these data do not establish clear causal links on their own between vascular dysfunction and critical power, the authors propose that reduced blood flow would limit oxygen delivery and waste removal from muscles and might additionally relate to impairments in muscle quality with age.

doi: 10.1113/EP091571

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