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2 : Death: Reverse

The reverse mortgage is intended to be the last loan that borrowers will ever need, so this is a question many homeowners and their heirs have on their minds as many of them intend to keep the loan and the home for life. If they do get a reverse mortgage and it does enable them to live in their homes without paying a mortgage payment for the rest of their lives

2 : Death: Reverse

And while there is never a payment due on a reverse mortgage, there is also no prepayment penalty so borrowers can choose to make a payment in any amount at any time without penalty but are not required to do so until the home is sold or they permanently move out of the property.

For example, borrowers who obtain a reverse mortgage under the payment option or the line of credit option but then do not draw large sums of money immediately or only draw a little now and then, will not accrue interest as fast as those who take a lump sum draw on the entire amount.

After the passing of the last surviving borrower, the reverse mortgage loan balance becomes due and payable. Many believe that the home reverts to the bank upon the death of the last borrower, but that is not the case.

Just as with a forward mortgage, when the loan is paid off all remaining equity stays with the heirs. If there is a shortfall in the amount owed and the current market value of the home, the heirs will own nothing, and the lender cannot look to any other assets to repay that money. FHA will cover any losses as all reverse mortgages are non-recourse loans.

There are no restrictions on sales to family members or otherwise, just in the case of a balance of the reverse mortgage being higher than the value of the property and heirs wanting the lender to forgive the over value portion of the loan and keep the property within the family.

Lenders are most happy when the loan is repaid and they do not have to become involved in foreclosure proceedings, but the nature of the loan is the last loan you will ever need and since most reverse mortgages do terminate with the death of the borrowers, foreclosure at termination is often the result when family members do not want to be involved in or have to wherewithal to repay the loan or sell the house.

Reverse mortgages are not multi-generational loans. If family members live with borrowers with reverse mortgages the day will come when that loan must be repaid, and those family members must plan for that eventuality well in advance.

Dune 2 needs to reverse the first movie's best death scene by bringing back Duncan Idaho (Jason Momoa). Idaho is a swordmaster in the service of House Atreides, and a close friend and confidant to Paul (Timothée Chalamet). During the events of Denis Villeneuve's first Dune movie, Idaho earned the love and intrigue of audiences with his easy, lighthearted charm which was only matched by his deadly abilities in combat. Tragically, however, Idaho dies by the end of the first Dune movie as he defends Paul and Jessica (Rebecca Ferguson) from a hoard of elite Sardaukar soldiers.

Mitochondrial DNA (mtDNA) depletion is involved in mtDNA depletion syndromes, mitochondrial diseases, aging and aging-associated chronic diseases, and other human pathologies. To evaluate the consequences of depletion of mtDNA in the whole animal, we created an inducible mtDNA-depleter mouse expressing, in the polymerase domain of POLG1, a dominant-negative mutation to induce depletion of mtDNA in various tissues. These mice showed reduced mtDNA content, reduced mitochondrial gene expression, and instability of supercomplexes involved in oxidative phosphorylation (OXPHOS) resulting in reduced OXPHOS enzymatic activities. We demonstrate that ubiquitous depletion of mtDNA in mice leads to predominant and profound effects on the skin resulting in wrinkles and visual hair loss with an increased number of dysfunctional hair follicles and inflammatory responses. Development of skin wrinkle was associated with the significant epidermal hyperplasia, hyperkeratosis, increased expression of matrix metalloproteinases, and decreased expression of matrix metalloproteinase inhibitor TIMP1. We also discovered markedly increased skin inflammation that appears to be a contributing factor in skin pathology. Histopathologic analyses revealed dysfunctional hair follicles. mtDNA-depleter mice also show changes in expression of aging-associated markers including IGF1R, KLOTHO, VEGF, and MRPS5. mtDNA-repleter mice showed that, by turning off the mutant POLG1 transgene expression, mitochondrial function, as well as the skin and hair pathology, is reversed to wild-type level. To our knowledge that restoration of mitochondrial functions can reverse the skin and hair pathology is unprecedented.

To help define the role of mtDNA depletion in aging and various diseases, we created an inducible mouse expressing, in the polymerase domain of POLG1, a dominant-negative (DN) mutation that induces depletion of mtDNA in the whole animal. Interestingly, skin wrinkles and visual hair loss were among the earliest and most predominant phenotypic changes observed in these mice. In the present study, we demonstrate that mtDNA depletion-induced phenotypic changes can be reversed by restoration of mitochondrial function upon repletion of mtDNA.

Aspartic acid to alanine amino acid change at the evolutionarily conserved site in the polymerase domain of POLG1 at 1135 position (D1135A-POLG1) (Fig. 1a) acts as a DN mutation, and its expression leads to decrease in mtDNA content and mitochondrial activity45, 46. We developed a Tet-inducible POLG1-DN mouse model with a ubiquitously expressed bidirectional promoter to control the expression of both POLG1-DN and green fluorescence protein (GFP)46. POLG1-DN-expressing mouse (Mouse I) was created by microinjection of the pTRE-Tight-BI-AcGFP1-D1135A-POLG1 construct into the one-cell stage egg from C57BL/6 mouse. The POLG1-DN-positive founder male mouse (Mouse I) was bred with the chicken β-actin-reverse tetracycline-controlled transactivator 3 (CAG-rtTA3) female mouse (Mouse II, Jackson Laboratories) to obtain the inducible POLG1-DN transgenic animal (Mouse III) (Fig. 1b). The presence of the DN POLG1, rtTA, and GFP were verified by polymerase chain reaction (PCR) genotyping (Fig. 1c). The rtTA3 was under the control of the ubiquitously expressed cytomegalovirus early enhancer element and CAG promoter. The POLG1-DN transgene was turned on by adding doxycycline (dox) in the food and/or drinking water when the mice were 8 weeks of age. The expression of GFP in POLG1-DN transgenic (mtDNA-depleter) animals was also verified by whole-body imaging for GFP after dox-mediated induction (Fig. 1d). The specificity of dox induction was verified by reverse transcription-PCR (RT-PCR) for the expression of POLG1 in the presence and absence of dox (Fig. 1e).

We conducted rescue experiment to substantiate that the mitochondrial dysfunction was the underlying cause for the alterations in the skin of mtDNA-depleter mice. Dox withdrawal restored mtDNA content to normal level in mtDNA-depleter mice. There was the induction of typical skin wrinkles and loss of hair in mtDNA-depleter mice (as shown in Fig. 9aii) after exposure to dox for 2 months. Then, after 1 month of dox withdrawal, the skin wrinkles and hair loss reverted, and the animals appeared relatively normal when compared to the age-matched wild-type animals (Fig. 9a). The histopathological analysis of the skin of phenotype-reversed (mtDNA-repleter) animals showed restoration of normal cutaneous structures (Fig. 9b). The epidermal hyperplasia (Fig. 9d), abnormal sebaceous glands, and defects in hair follicle development and hair shaft formation were absent in the mtDNA-repleter mice (Fig. 9b). The number of anagen hair follicles reverted to the wild-type levels (Fig. 9f), and the number of hair follicles in telogen also decreased in the mtDNA-repleter mice compared with mtDNA-depleter mice (Fig. 9e). We also observed a significant decrease in the inflammatory infiltrate present in the skin of phenotype-reversed animals (Fig. 9b, c, g). The macrophages, granulocytes, and B lymphocyte and T lymphocyte that were present in the skin of mtDNA-depleter mice (Fig. 7a) were predominantly absent in the skin of the mtDNA-repleter mice (data not shown). We observed a reversal of mtDNA content (Fig. 9h) and the expression of mtDNA-encoded genes (Figs. 2d and 9i). Expression of genes involved in the skin inflammation and wrinkling also reverted to the levels in wild-type animals (Figs. 7c, d and 9j). These observations suggest that mitochondrial dysfunction-induced phenotypical, histopathological, and molecular changes can be reversed by restoration of mitochondrial function.

Accumulating evidence suggests a strong link between mitochondrial dysfunction, mitochondrial diseases, aging, and aging-associated diseases26, 28, 30, 38, 63. Notably, increased somatic mtDNA mutations and decline in mitochondrial functions have been extensively reported during human aging26, 28, 30. Studies also suggest a decrease in mtDNA content and mitochondrial number with age32, 33, 64. The major finding of our study is that the ubiquitous depletion of mtDNA predominantly leads to wrinkled skin and hair loss accompanied by inflammatory phenotype. Wrinkled skin and hair loss are obvious features of skin aging and aging-associated phenotypic changes in humans. We discovered that these aging-associated phenotypic changes could be reversed by restoring mtDNA content to wild-type level. To our knowledge this observation is unprecedented.

Loss of collagen fibers is reported to underlie skin wrinkles58. A tight balance between the proteolytical enzymes MMPs and their tissue-specific inhibitor TIMP1 is essential to maintain the collagen fiber content in the skin59. Expression of MMPs is altered in the aged skin66, 67. Consistent with these reports, the skin of mtDNA-depleter mice showed increased expression of MMPs and decreased expression of TIMP1, indicating loss of balance contributing to the development of skin wrinkles (Fig. 7d). Repletion of mtDNA content restored MMP expression (Fig. 9j) leading to a reversal of wrinkled skin and hair loss (Fig. 9a, b). These experiments show that mitochondria are regulators of skin aging and loss of hair. This observation is surprising and suggests that epigenetic mechanisms underlying mitochondria-to-nucleus cross-talk must play an important role in the restoration of normal skin and hair phenotype. Further experiments are required to determine whether phenotypic changes in other organs can also be reversed to wild-type level by restoration of mtDNA. 041b061a72


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