Recent studies have revealed that decline in cellular nicotinamide adenine dinucleotide (NAD+) levels causes aging-related disorders and therapeutic approaches increasing cellular NAD+ prevent these disorders in animal models. The administration of nicotinamide mononucleotide (NMN) has been shown to mitigate aging-related dysfunctions. However, the safety of NMN in humans have remained unclear. We, therefore, conducted a clinical trial to investigate the safety of single NMN administration in 10 healthy men of 40 to 60 years of age.

A single-arm non-randomized intervention was conducted by single oral administration of 100, 250, and 500 mg NMN. Clinical findings and parameters, and the pharmacokinetics of NMN metabolites were investigated for 5 hours after each intervention. Ophthalmic examination and sleep quality assessment were also conducted before and after the intervention.

The single oral administrations of NMN did not cause any significant clinical symptoms or changes in heart rate, blood pressure, oxygen saturation, and body temperature. Laboratory analysis results did not show significant changes, except for increases in serum bilirubin levels and decreases in serum creatinine, chloride, and blood glucose levels within the normal ranges, independent of the dose of NMN. Results of ophthalmic examination and sleep quality score showed no differences before and after the intervention. Plasma concentrations of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-5-carboxamide were significantly increased dose-dependently by NMN administration. The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects. Thus, the oral administration of NMN was found to be feasible, implicating a potential therapeutic strategy to mitigate aging-related disorders in humans.

You are an entrepreneur who wishes to start a longevity industry biotech startup, but your experience to date is in a different industry. This document is an initial primer and guide to help you get started. New classes of therapy, targeting the mechanisms of aging, have the potential to prevent and reverse all age-related disease, and greatly extend healthy human lifespan. The first rejuvenation therapies are already under clinical development in numerous startup companies. This new longevity industry is growing exceptionally rapidly. Venture funding for longevity startups is increasing enormously year over year. Yet there are far too few entrepreneurs and new startups in comparison to the available funding. Your arrival will be welcomed: this is a friendly, and close-knit community.

You are entrepreneurial. You have heard the buzz about the new longevity industry: the rapid growth in funding, the numerous billionaires becoming involved, the new approaches to medicine that are targeting the mechanisms of aging to prevent and reverse the diseases and frailty of old age. You want to get involved, to start a company, to do something about aging ... to change the world for the better. But how? Whatever your past industry, here you must be the business co-founder. Life science and its application to biotechnology is a vast, complex, intimidating field. Aging is its own highly specialized portion of that field. You need an understanding sufficient to identify a project to work on; you need a scientific co-founder; you need to know the investors and the movers and shakers. Where to even start?

This document is a starting point. We hope that it helps.

Cellular senescence is a terminal cell response consisting on the implementation of a permanent cell cycle arrest and the acquisition of a secretory phenotype with cell-to-cell communication properties. Exhaustion of the proliferative capacity of the cell leads to senescence, and the accumulation of these damaged cells in tissues from old individuals is considered a key element in the process of aging. Despite this detrimental effect, the senescence response has a beneficial side protecting damaged cells from proliferating. This is considered the basis of its tumor-suppressive function. The recent discovery of developmentally programmed cell senescence during embryogenesis expanded our view of the positive activities of this response. Senescence during development promotes cell turnover, tissue remodeling, and, paradoxically, growth. A similar positive pro-morphogenetic activity for cell senescence has been suggested to operate during skin wound healing in mice and during limb regeneration in salamanders. Senescent cells seem to appear at wound sites after injury to help promote optimal wound healing.

Here, we decided to evaluate the senescence response in the context of tissue injury using an animal model of complex tissue regeneration, the zebrafish. To study senescence after tissue damage, we amputated the pectoral fin of adult fish (around 1 year old) at approximately 50% of its length and followed regeneration with time. We stained fins for senescence-associated beta-galactosidase (SAbetaGal), the most widely used marker of senescence, after 8, 16, or 30 days postamputation (dpa), a time point in which fins were completely regenerated. Fins at 8 dpa showed intense blue staining compared with light blue at 16 dpa and completely absent staining at 30 dpa. We observed that 8 dpa was the time point that produced a stronger SAbetaGal reaction and this activity was restricted to the distal part of the fin, the area where regeneration takes place. These results support the notion of a transient induction of cell senescence during fin regeneration.

To directly assess the role of senescence induction during fin amputation, we decided to induce the removal of these senescent cells from amputated fins. For this, we treated fish for 48 or 72 hr with ABT-263 (Navitoclax), a senolytic compound that by inhibiting the Bcl-2 antiapoptotic family of proteins triggers specifically the death of the senescent cell. ABT-263 treatment caused a reduction in SAbetaGal staining and a concomitant induction of apoptosis in the regenerating area. We determined the regenerative capacity by measuring the length of regenerate at 8 dpa in fish treated with ABT-263. This analysis revealed that the removal of senescent cells by ABT-263 treatment clearly impaired regeneration, with amputated fins in fish treated with ABT-263 showing a clear reduction in the length of regenerate compared with the one reached in control animals.

Underdog Pharmaceuticals, Inc. (Underdog), and SENS Research Foundation (SRF) today announced the launch of Underdog and the completion of its seed round, providing 3.95 million to promote Underdog's development of disease-modifying treatments for atherosclerosis and other age-related diseases. SRF also announced two senior appointments. The Underdog round is led by Michael Greve's Kizoo Technology Capital, part of the Forever Healthy Group and one of the premier organizations focusing on accelerating rejuvenation biotechnologies.

Underdog was built from an SRF flagship program that has driven two years of applied development designed to explore and repair the underlying causes of cardiovascular disease. Its co-founders are Matthew O'Connor, Ph.D. and Michael Kope, formerly the V.P. of Research and the founding CEO, respectively, of SRF. "We've taken a well-known and extremely safe compound, and have created novel derivatives that can specifically target the toxic biomolecule that drives the development of atherosclerosis, the cause of most heart attacks and strokes." Underdog's research has combined computational and synthetic chemistry programs to create custom-engineered cyclodextrins (polysaccharides with known industrial and pharmaceutical uses) to capture, and remove from cells, oxidized cholesterol derivatives such as 7-ketocholesterol, which are broadly toxic molecules with no known biological function.

Who are the Underdog Pharmaceuticals team, and how did you all become involved in this business of defeating atherosclerosis?

Underdog is being co-founded by Michael Kope and myself, formerly the founding CEO and VP of Research, respectively, of SRF. We are exiting our decade-long service at SRF to do this. We are building a great team of researchers and partners including our home-grown computational chemist Amelia Anderson and veteran bench industry biologists Daniel Clemens and Tamari Kirtadze. We are partnering with Cyclolab LTD for cyclodextrin chemistry expertise, MD.USE for cyclodextrin computational chemistry, and Biolacuna for regulatory affairs.

Amelia Anderson was one of our elite SRF Summer Scholars two years ago. It was that summer that she conceived of our computational chemistry program and started to build it. Dave Brindley, founder of Biolacuna, was the first SRF-sponsored PhD student and has since become a world-renowned biomedical regulatory expert specializing in developing methods for gaining approval of the new classes of rejuvenation biotechnologies that are going to be needed to revolutionize medicine. SRF's investment in education is really coming home to help us.

Every name has a story, why Underdog Pharmaceuticals?

We chose the name Underdog to connote our core mission - to attack the underlying causes of age-related disease; and also to represent the broader fight as the underdog seeking to overturn the current costly and inefficient paradigm for the treatment of such diseases ... and because Mike and I couldn't otherwise agree on whose dog to name the company after.

You outlined the science behind Underdog at Undoing Aging earlier this year, but if you could give a summary for the audience here?

We are targeting 7-ketocholesterol (7KC) in aging and disease. 7KC is a toxic oxysterol formed by the reaction of a cholesterol molecule with an oxygen free radical. 7KC has no redeeming qualities and is difficult to clear once it has become lodged in a cell. It is highly toxic to cells and as a fundamental damage molecule implicated many diseases of aging including atherosclerosis (and therefor heart attacks and strokes), Alzheimer's disease, and macular degeneration. We are engineering cyclodextrins to bind 7KC with high affinity and specificity. Cyclodextrins are cyclic sugar molecules that are very safe and amenable to engineering. We have created a new class of cyclodextrins that can bind 7KC more than ten times better than any other cyclodextrin currently available. The goal is to remove 7KC from cells and tissues and have it be excreted from the body.

Do you plan to work towards sequestration of other molecular targets via cyclodextrins, now that you've demonstrated success with one?

Yes! The tools that we are developing are quite amenable to targeting other damage molecules with cyclodextrins. Particularly the cyclodextrin computational platform that we are developing can easily be adapted for other targets; as well as our automated cyclodextrin screening tool and safety testing assays. For at least the next few years, however, we'll be spending 99% of our time and energy on getting our first drug to the clinic.

SENS Research Foundation is a non-profit, Underdog Pharmaceuticals is a startup; has it been challenging to make the shift to the for-profit world?

It has not. SRF's mission has always been to bring the promise of rejuvenation biotechnologies to real-life people. The organization has always known that successful technology transfer is inherent and intimate to that mission. SRF has always been looking for opportunities for translation with all of our projects. With respect to Underdog this transition for us has been been super fun. We've been delighted with the response to our research from the scientific community, discussions with financial agents, and with our development collaborators all around the world. We have an exciting message and it's been gratifying to see how enthusiastically it's been received. Our investors are all enthusiastic about our mission which is why we've been able to raise the funds that we need and transition so quickly into this new company.

Is this the starting point for SENS Research Foundation to become an incubator of a series of biotech startups?

SRF won't be developing wholly owned subsidiaries; it will be creating companies using the same rubric as university tech transfer programs. As with Underdog, SRF would have both royalty and equity interests in such companies. It is inherent to the mission that SRF tries to do this to make these technologies publicly available, and indeed we think one sees evidence of that both in the success of this spinout and in the new leadership that's been chosen for SRF. Jim O'Neill is the new interim CEO at SRF. He has an extensive background in both government research funding and private investment and is committed to driving this push towards translating SRF technologies into therapies. Professor Alexandra Stolzing is coming on board to replace me as VP of Research. Her reputation in rejuvenation / regenerative medicine should need no introduction, but she has played both faculty and private industry leadership roles focused on translational medicine in aging. SRF is in the process of reviewing incubator and accelerator programs focused on translating SENS-style damage repair technologies. We'd love to see them do more of that!

Will we see the allotopic expression project spun out in the same way?

The MitoSENS allotopic expression project is plowing ahead. It started as a basic research program but has made great strides and could be ready to make a transition to the treatment of mitochondrial genetic disease quite soon.

If this all works out amazingly well, atherosclerosis is much reduced, and Underdog Pharmaceuticals becomes a high valuation public company, what next?

Well we want to not only reduce atherosclerosis, but eliminate it entirely! But on a broader scale our team genuinely hopes to be able to contribute to a change in paradigm, from both a regulatory perspective and a clinical perspective, on how we treat diseases of aging. This could be a long-term challenge, and if done appropriately, we, together with other companies with similar missions, can work with regulatory agencies to look at age-related disease in a new way. This is a big part of the reason that we want to do this company now.

Macroautophagy, a key player in protein quality control, is proposed to be systematically impaired in distinct tissues and causes coordinated disruption of protein homeostasis and ageing throughout the body. Although tissue-specific changes in autophagy and ageing have been extensively explored, the mechanism underlying the inter-tissue regulation of autophagy with ageing is poorly understood. Here, we show that a secreted microRNA, mir-83, homologous to mammalian miR-29, controls the age-related decrease in macroautophagy across tissues in Caenorhabditis elegans.

Upregulated in the intestine by hsf-1 with age, mir-83 is transported across tissues potentially via extracellular vesicles and disrupts macroautophagy by suppressing CUP-5, a vital autophagy regulator, autonomously in the intestine as well as non-autonomously in body wall muscle. Mutating mir-83 thereby enhances macroautophagy in different tissues, promoting protein homeostasis and longevity.

Our results not only show that a secreted microRNA is an inter-tissue messenger controlling autophagy for protein homeostasis but also indicate that tissues other than the nervous system (e.g., the intestine) broadcast signals for protein homeostasis throughout the body. Similarly, transcellular chaperone signaling from muscle to intestine and neurons is important in the response against proteotoxic stress.

Age-related changes in the cerebrovascular system include structural reorganization of the vascular beds, reduced vessel elasticity, and disintegration of the blood-brain barrier. Further observations include reduced cerebral perfusion, and increased lesion burden in the cerebral white matter. Lesions can be observed as white-matter hyperintensities (WMHs) upon magnetic resonance imaging (MRI). They arise from ischemia, hypoperfusion, blood-brain-barrier breakage, and inflammation and are considered manifestations of cerebral small-vessel disease. WMHs are highly prevalent in aging and predictive of broad-ranged cognitive decline, dementia, and mortality.

Dopamine (DA) has been identified as an important modulator of cognitive functions. Maladaptive DA signaling typically gives rise to cognitive impairment, whereas increased DA transmission, if not excessive, may improve performance. Numerous positron emission tomography (PET) studies have demonstrated reduced availability of DA constituents in older individuals, with links to reduced cognitive performance. The age sensitivity of the DA system has therefore been suggested to modulate cognitive trajectories in aging. Research suggests relationships among vascular function, DA status, and atrophy in pathological and normal aging. Cognitive impairments in Parkinson's disease (PD) have been related to deficits in perfusion and DA decline, which are exacerbated in presence of WMHs. Increased WMH burden in normal aging is paralleled by decreased grey-matter and white-matter volume, and has been associated with reduced DA transporter and D1 receptor availability.

Thus we evaluated the interrelation among WMH burden, cerebral perfusion, DA D2-receptor (D2DR) availability, grey- and white-matter structure, and cognition in 181 healthy, older adults aged 64-68 years. Higher cardiovascular risk as assessed by treatment for hypertension, systolic blood pressure, overweight, and smoking was associated with lower frontal cortical perfusion, lower putaminal D2DR availability, smaller grey-matter volumes, a larger number of white-matter lesions, and lower episodic memory performance. Taken together, these findings suggest that reduced cardiovascular health is associated with poorer status for brain variables that are central to age-sensitive cognitive functions, with emphasis on DA integrity.

Several neurodegenerative diseases involve the slow accumulation of a misfolded protein in neurons over many years. The proteins involved in these diseases might differ, but the result is similar - eventually, the neurons die from the build-up of toxic misfolded proteins. Scientists have long been searching for ways to reduce the levels of the disease-driving proteins without also clearing their wild-type counterparts, which typically have myriad crucial functions. Researcher snow show that this can be accomplished using compounds that interact specifically with both the misfolded part of the protein and the neuron's protein-clearance machinery.

The researchers chose to focus on Huntington's disease, which is caused by an abnormally long stretch of glutamine amino-acid residues in the huntingtin (HTT) protein. This expanded polyglutamine tract causes HTT to misfold. Cells are able to degrade the mutant huntingtin (mHTT) through autophagy - a clearance mechanism that involves engulfment of proteins by a vesicle called the autophagosome. Researchers hypothesized that compounds that bind to both the mutant polyglutamine tract and the protein LC3B, which resides in the autophagosome, would lead to engulfment and enhanced clearance of mHTT. But no such compounds had been reported. The authors therefore conducted small-molecule screens to identify candidate compounds.

Researchers initially identified two candidates, dubbed 10O5 and 8F20. These compounds had been shown to inhibit, respectively, the activity of the cancer-associated protein c-Raf and kinesin spindle protein (KSP), which has a key role in the cell cycle. The team found that 10O5 and 8F20 were able to clear mHTT independently of their effects on these other proteins. The researchers showed that the regions of 10O5 and 8F20 that interacted with mHTT and LC3B in the screen shared structural similarities. Next, they screened for compounds that shared these structural properties but were structurally distinct. This led them to discover two more compounds, AN1 and AN2, that link mHTT to LC3B and thereby selectively reduce levels of mHTT.

Researchers validated their discovery by showing that the four compounds reduced levels of the full-length mHTT protein (not just the protein fragment used in the screen). The compounds lowered levels of mHTT both in vitro - in mouse neurons and neurons derived from the biopsied skin cells of people with Huntington's disease - and in vivo, in mouse and fly models of the disease.

A 2015 large-scale retrospective cohort study of nearly 2 million people from the United Kingdom Clinical Practice Research Datalink showed that the incidence of dementia continued to fall for every increasing BMI category. Two Mendelian randomization studies showed no association between obesity and dementia. BMI is not a perfect measure of adiposity because it cannot discriminate between fat and lean body mass. Waist circumference is a more accurate indicator of abdominal visceral fat level than body mass index (BMI) in the elderly. Studies have been limited, however, and focused on the relationship between waist circumference and dementia in older persons. One study showed that central adiposity, represented by waist circumference, predicted an increased risk for cognitive decline during a 2-year follow-up period in older patients with diabetes. Another study reported that waist circumference was correlated with lower overall cognition and executive performance in older women with type 2 diabetes.

To help determine a healthy waist circumference, researchers compared relative risk of dementia associated with waist circumference and BMI categories using the Korea National Health Insurance Service program. The program is a mandatory social health insurance program that enrolls about 98 percent of Koreans who participate in biannual standardized health examinations. The study population comprised 872,082 participants aged 65 years and older who participated in the Korean national health screening examination between January 1, 2009 and December 31, 2009. The study population was observed from baseline until the date of development of dementia, death, or until December 31, 2015, whichever came first.

The results of the study showed participants with a waist circumference of greater than or equal to 90cm for men and 85cm for women had a significantly increased risk of dementia after adjusting for other factors such as age, BMI, blood pressure, cholesterol, liver function tests and various lifestyle factors. As for the association between BMI categories with dementia in older men and women who were underweight, they experienced a significant increased risk of dementia compared with normal weight individuals after factoring in comorbidities and various lifestyle factors. The relationship with BMI and dementia may be a result of the adverse effects of sarcopenia in the elderly.

In recent years, promising therapeutic approaches to treat osteoporosis are mainly focused on targeting the functions of skeletal stem cells and osteoblasts. A more detailed understanding of bone biology has led to the discovery of novel therapeutic targets with enhanced molecular insights into the communication between bone-forming osteoblasts and bone-resorbing osteoclasts as well as the orchestrating signaling network. Thus, it is necessary to develop new approaches to stimulate osteoblast activity. In the present study, we demonstrate that bone marrow stem cell (BMSC) derived exosomes carrying the long non-coding RNA (lncRNA) MALAT1 could effectively stimulate the osteoblast activity. Our results highlighted the potential of exosomal MALAT1 to prevent osteoporosis in mouse models.

A key finding of the current study indicated that BMSCs-derived exosomal MALAT1 could potentially promote osteoblast activity. Exosomes could actively transport and transfer information between miRNAs, proteins, and mRNAs to target cells, thus affecting their behaviors and strongly modifying the entire microenvironment. Consistent with previous reports, we observed the protective role of exosome-mediated delivery of MALAT1 in disease. Furthermore, we detected that the upregulation of MALAT1 could attenuate the symptoms of osteoporosis in mice. Existing literature has suggested that lncRNAs play critical roles in the initiation and pathogenesis of osteoporosis. For instance, a recent study demonstrated that lncRNA MEG3 suppressed the osteogenic differentiation of mesenchymal stem cells in postmenopausal osteoporosis.

Our study provides evidence that BMSC-derived exosomal MALAT1 may contribute to enhanced osteogenic activity and alleviated symptoms of osteoporosis in the mouse model by acting as a miR-34c sponge to upregulate SATB2 expression. These results provide a broader understanding of the pathogenesis of osteoporosis as well as novel therapeutic strategies for its treatment.

Inflammaging was recently affiliated with the progression of diabetic complications. Local cellular senescence together with senescence-associated secretory phenotype (SASP) are the main contributors to inflammaging. However, little is known about their involvement in diabetic periodontitis. Gingiva is the first line of host defense in the periodontium, and macrophages are key SASP-carrying cells. Here, we explored the molecular mechanism by which hyperglycemia drives the inflammaging in the gingival tissue of diabetic mice and macrophages.

We demonstrated that hyperglycemia increased the infiltrated macrophage senescence in gingival tissue of diabetic mice. Simultaneously, hyperglycemia elevated the local burden of senescent cells in gingival tissue and induced the serum secretion of SASP factors in vivo. Moreover, in vitro, high glucose induced macrophage senescence and SASP factors secretion through phosphorylation of NLRC4, which further stimulated the NF-κB/Caspase-1 cascade via IRF8-dependent pathway.

Deletion of NLRC4 or IRF8 abolished hyperglycemia-induced cellular senescence and SASP in macrophages. In addition, we found that treatment with metformin inhibited NLRC4 phosphorylation and remarkably decreased cellular senescence and SASP in the context of hyperglycemia. Our data demonstrated that hyperglycemia induces the development of inflammaging in gingival tissue and suggested that NLRC4 is a potential target for treatment of diabetes-associated complications.

Cerebrovascular dysfunction and cognitive decline are highly prevalent in aging, but the mechanisms underlying these impairments are unclear. Cerebral blood flow decreases with aging and is one of the earliest events in the pathogenesis of Alzheimer's disease (AD). We have previously shown that the mechanistic target of rapamycin (mTOR) drives disease progression in mouse models of AD and in models of cognitive impairment associated with atherosclerosis, closely recapitulating vascular cognitive impairment. In the present studies, we sought to determine whether mTOR plays a role in cerebrovascular dysfunction and cognitive decline during normative aging in rats.

Using behavioral tools and MRI-based functional imaging, together with biochemical and immunohistochemical approaches, we demonstrate that chronic mTOR attenuation with rapamycin ameliorates deficits in learning and memory, prevents neurovascular uncoupling, and restores cerebral perfusion in aged rats. Additionally, morphometric and biochemical analyses of hippocampus and cortex revealed that mTOR drives age-related declines in synaptic and vascular density during aging. These data indicate that in addition to mediating AD-like cognitive and cerebrovascular deficits in models of AD and atherosclerosis, mTOR drives cerebrovascular, neuronal, and cognitive deficits associated with normative aging.

Thus, inhibitors of mTOR may have potential to treat age-related cerebrovascular dysfunction and cognitive decline. Since treatment of age-related cerebrovascular dysfunction in older adults is expected to prevent further deterioration of cerebral perfusion, recently identified as a biomarker for the very early (preclinical) stages of AD, mTOR attenuation may potentially block the initiation and progression of AD.

Alzheimer's disease (AD) is a complex, multi-factorial disease affecting various brain systems. This complexity implies that successful therapies must be directed against several core neuropathological targets rather than single ones. The scientific community has made great efforts to identify the right AD targets beside the historic amyloid-β. Neuroinflammation is re-emerging as determinant in the neuropathological process of AD. A new theory, still in its infancy, highlights the role of gut microbiota in the control of brain development, but also in the onset and progression of neurodegenerative diseases.

Bidirectional communication between the central and the enteric nervous systems, called gut-brain axes, is largely influenced by gut microbiota and the immune system is a potential key mediator of this interaction. Growing evidence points to the role of gut microbiota in the maturation and activation of host microglia and peripheral immune cells. Several recent studies have found abnormalities in gut microbiota (dysbiosis) in AD populations. These observations raise the intriguing question whether and how gut microbiota dysbiosis could contribute to AD development through action on the immune system and whether, in a therapeutic prospective, the development of strategies preserving a healthy gut microbiota might become a valuable approach to prevent AD.

Cardiovascular diseases are the leading cause of mortality and morbidity worldwide, including in many low- and middle-income countries (LMICs). India has experienced a rapid epidemiological transition, resulting in notable prevalence of hypertension, diabetes, and obesity. India is also affected by high levels of ambient and household air pollution (HAP), resulting in a setting with high baseline cardiovascular risk and widespread exposure to high levels of air pollution.

Long-term exposure to ambient particulate matter (PM) has been associated with risk of acute myocardial infarction, stroke, and cardiovascular mortality. The most plausible pathway by which PM causes cardiovascular diseases is by promoting inflammation and atherosclerosis. Atherosclerosis is a systemic vascular disease representing the aging process and the cumulative adaptive response to cardiovascular risk factors (e.g. hypertension, diabetes). Carotid intima-media thickness (CIMT) is a non-invasive, surrogate marker of subclinical atherosclerosis, associated with cardiovascular risk factors, events, and mortality. There is evidence for a positive association between long-term ambient PM and CIMT. However, the magnitude of associations has been heterogeneous and studies are limited to high-income countries with low or moderate levels of air pollution. Additionally, the evidence for the association between HAP and CIMT is limited.

To our knowledge, there is no previous evidence about the association between outdoor ambient fine particulate matter (PM) and CIMT from populations in low- and-middle income countries. In this population-based study of 3372 participants, with annual mean ambient PM of 32.7 µg/m3, annual mean PM was associated with carotid intima-media thickness among men. 60% of participants used biomass cooking fuel, which was strongly associated with carotid intima-media thickness in women cooking with an unvented stove. Women had higher values of carotid intima-media thickness compared with men, which might be attributed to high cumulative exposure to household air pollution.

Parkinson's disease (PD) is a highly heterogeneous disorder, which probably consists of multiple subtypes. Aggregation of misfolded alpha-synuclein and propagation of these proteinacious aggregates through interconnected neural networks is believed to be a crucial pathogenetic factor. It has been hypothesized that the initial pathological alpha-synuclein aggregates originate in the enteric or peripheral nervous system (PNS) and invade the central nervous system (CNS) via retrograde vagal transport. However, evidence from neuropathological studies suggests that not all PD patients can be reconciled with this hypothesis. Importantly, a small fraction of patients do not show pathology in the dorsal motor nucleus of the vagus.

Here, it is hypothesized that PD can be divided into a PNS-first and a CNS-first subtype. The former is tightly associated with REM sleep behavior disorder (RBD) during the prodromal phase and is characterized by marked autonomic damage before involvement of the dopaminergic system. In contrast, the CNS-first phenotype is most often RBD-negative during the prodromal phase and characterized by nigrostriatal dopaminergic dysfunction prior to involvement of the autonomic PNS. The existence of these subtypes is supported by in vivo imaging studies of RBD-positive and RBD-negative patient groups and by histological evidence. The present proposal provides a fresh hypothesis-generating framework for future studies into the etiopathogenesis of PD and seems capable of explaining a number of discrepant findings in the neuropathological literature.